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181 Cards in this Set

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Picornavirus - 1. structure/properties; 2. Transmission/life cycle; 3. Types
1. 22-30nm, isocohedral, +ssRNA, non-enveloped, PH stability, mostly non-systemic; 2. Wide variety of cellular receptors, Life cycle -- Virus binds to R --> genome is injected through virion across cell membrance.; 3. includes Genus enterovirus, Genus parechovirus (3types), genus heparnavirus (1type), genus rhinovirus, hepatovirus (HepA)
Genus enterovirus - subtypes include? Tx?
Includes polio, coxsackie, echo, enteroV. Tx -- Virus attchment (block R -- AB, chemicals), Viral entry and genome release (Pleconaril), Protease processing (Ruprintrivir), RNA-dependent RNA polymerase Inhib (Ribavirin)
RNA-dependent RNA inhibitor?
Ribavirin
Proease processing? (Tx for virus attacks)
Ruprintrivir
"polythetic" taxonomic method of Virology
any given virus group is described using a collection of individual properties. "a class whose members always have several properties in common although no single common attribute is present in all of its members"
Baltimore Classification of Virus genome type
Class I -- ds DNA; Class II -- +ssDNA, Class III -- ds RNA (reovirus); Class IV -- +ssRNA (--> -RNA --> +mRNA); Class V -- -ssRNA (--> +mRNA); Class VI -- +ssRNA (-->-DNA --> +/-DNA)
RNA viruses -- related human dz: 1. Paramyxoviridae; 2. Orthomyxoviridae; 3. Coronaviridae; 4. Arenaviridae; 5. Rhabdoviridae; 6. Filoviridae; 7. Bunyaviridae; 8. Retroviridae; 9. Reoviridae; 10. Picornaviridae; 11. Togaviridae; 12. Flaviviridae; 13. Noroviridae; 14. Delta
RNA viruses -- related human dz: 1. Paramyxoviridae -- measles, mumps, RSV; 2. Orthomyxoviridae -- Influenza virus A,B, and C; 3. Coronaviridae -- Coronavirus, SARS; 4. Arenaviridae -- Lassa fever virus; 5. Rhabdoviridae -- Rabies; 6. Filoviridae -- E.boli and Marburg virus; 7. Bunyaviridae -- Hanta virus; 8. Retroviridae -- HIV, Human T-cell leukemia virus Types I and II; 9. Reoviridae -- Rota virus; 10. Picornaviridae -- rhinovirus, poliovirus, coxsackievirus, hepatitis A virus; 11. Togaviridae -- Rubella virus ("German measles"); 12. Flaviviridae -- yellow fever, dengue virus, St. Luis virus, West Nile virus, Hepatitis C virus; 13. Noroviridae -- Norwalk virus, calicivirus; 14. Delta -- Delta agent
DNA viruses -- 1. Poxviridae; 2. Herpesviridae; 3. Adenoviridae; 4. Hepadnavridae; 5. Polyoma viridae; 6. Papilloma viridae; 7. Parvoviridae
DNA viruses -- 1. Poxviridae -- smallpox virus, vaccinia virus, monkeypox virus, molluscum contgiosum virus; 2. Herpesviridae -- HSV type 1&2, varicella-zoster virus (chicken pox), EBV, CMV, HHV 6,7, and 8 (KSHV); 3. Adenoviridae -- Adenovirus; 4. Hepadnavridae -- Hepatitis B virus; 5. Polyoma viridae -- JC virus, BK virus, SV40; 6. Papilloma viridae -- Papilloma virus; 7. Parvoviridae -- Parvovirus B19, adeno-associated virus
Plaque Assay vs. Focus assay?
Plaque assay -- tissue culture assay for quantitating infectious virus; Focus assay -- for viruses that induce cell proliferation
Neutralizing AB acts on what step of viral life cycle?
Virion attachment stage. Interfere the interaction of Cell surface receptors and viral surface proteins.
Viral receptors: 1. HIV; 2. EBV; 3. Rhinovirus; 4. Influenza V
1. HIV -- Human CD4 on T cells; 2. EBV -- Human complement receptor CD21; 3. Rhinovirus -- human ICAM-1; 4. Influenza virus -- Sialic acid
Virion entry -- difference between Endocytosis and fusion
Endocytosis -- used by naked viruses. surrounded by endosomal membrane. NO trace of viral proteins left behind; Fusion -- released capsid into cytoplasm, leaving traces of viral proteins in the plasma membrane. Some enveloped viruses are taken up by endocytosis, and fusion of their membrane with the membrane of an acidic endosomal compartment released the capsid into the cytoplasm.
Virus release from host -- difference b/w Naked virus vs. Enveloped virus
Naked -- cell lysis required for release and dissemination of new virions; Enveloped -- by budding at the plasma membrane. capsid assembly and release occur in a coupled process at the plasma membrane for most.
Outcomes of virus infection at the Cellular level: 1. Productive infxn; 2. Latent infxn; 3. Persistent infxn; 4. Abortive infxn
1. Productive infxn -- generally leads to cytopathic effect with a burst of virus production; 2. Latent infxn -- NO production of infectious virus particles but genetic information of virus remains (ex. Chicken pox infxn); 3. Persistent infxn -- chronic virus production (ex. Hep C); 4. Abortive infxn -- virus life cycle incomplete and virus lost.
Virus effect on host cell -- (3 types)
1. Acute cytopathic effect -- membrane fusion of adjacent cells to form giant, multi-nucleate cells (syncytia), shut off of host metabolism, induction of apoptosis, cell death (necrosis); 2. Cell transformation -- loss of normal growth control, "oncogenic potential"; 3. No apparent effect.
Outcomes of virus infection at the Organismic level: types?
1. Inapparent infxn; 2. Acute infxn; 3. Latent recurrent infxn; 4. Persistent infxn
Syncytia?
giant, multinucleated cells produced by membrane fusion of adjacent cells by virus
Perenteral?
Type of transmission -- blood borne direct contact
Host defense to viral infxn -- 4 types
1. Innate response -- Soluble mediators (IFNs, cytokines, chemokines, antiviral response within infxted cell make surrounding cells resistant to infxn, recruit effector cells like NK cells and macrophages), Apoptosis (to avoid release of infectious virus); 2. Adaptive response (humoral) -- neutralizing AB (block attachment or entry), complement fixing AB (lyse virions or infected cells); 3. Adaptive response (cell-mediated) -- MHC presentation of viral peptides (killing of virus-infected cells by cytotoxic T cells); 4. Memory response (B & T cells) -- resist infxn.
PH stability of: 1. Enterovirus; 2. Rhinovirus
1. Enterovirus -- stable at pH 3-9; 2. Rhinovirus -- unstable below pH 6
Hand, Foot and mouth dz -- cause & sx
Coxsackie A 16, occasionally other Coxsackie A viruses and Enterovirus 71. Sx -- Mild fever, sore throat, fatigue, loss of appetite, vesicular lesions
Acute hemorrhagic conjunctivitis -- cause & sx
Coxsackie A viruses (A24, 28), Enterovirus 70; Sx -- rapid onset of watery discharge, foreign body sensation, burning, photophobia
Pleurodynia, Bornholm's dz, "devil's grip"
Coxsackie B viruses (likes to go to muscles). Sx -- sudden onset of fever, severe epigastric or thoracic pain. Prognosis -- lasts 2-4 days but may relapse and sx may recur for several weeks.
Herpangina
Coxsackie viruses; Sx -- sudden onset of fever, sore throat, headache, anorexia, vesicular ulcerated lesions, generally occuring in the back of the throat around the tonsils and rear portion of palate. (Except sudden onset of fever, Sx is same as Hand, Food, and Mouth dz (they have MILD fever)
Enterovirus 71 -- characteristics, dz
an emerging pathogen. Outbreaks in many part of world. Hand,foot,and mouth dz. Paralysis, Myocarditis. Several fatal cases
Polio -- 4 types of clinical outcome
1. Inapparent (subclinical) infxn -- 90-95%; 2. Mild (minor) illness -- 4-8%, minor undifferentiated febrile illness (occasional UR infxn, influenza-like illness, gastroenteritis); 3. Aseptic meningitis -- nonparalytic polio, 1-2%, minor illness progress to CNS invasion, stiffness and pain in back and nexk. lasts 2-10 days; rapid and complete recovery; 4. Paralytic poliomyelitis - 0.1-0.2%, polios (gray), myelos (marros), initial nonspecific febrile illness, spectrum of paralytic dz variable, Sx - asymmetric flaccid paralysis, lower extremeties > upper extermeties, large muscle groups more involved, Bulbar paralysis (cranial nerves, medulla, respiratory compromise, death 5% overall), slow recovery (2 yrs for 100%), complications (residual paralysis); 5. Post-polio syndrome (due to death of individual nerve terminals in the motor units that remain after the initial attack)
Dx -- ptn had a cold --> now feel stiffness in back and neck
Think Polio -- Aseptic meningitis
Poliovirus -- pathogenesis & pathology
Virus entry --> alimentary tract and multiplies locally (tonsil, Peyer's pathces). Present mostly in Pharynx (1-2 wks after infxn). secreted in stools for serveral wks. Small Intesting -- invasion and multiplication. Mesenteric LN -- multiplication. Primary viremia spread via Bood stream. Other tissues infected -- LN, brown fat, CNS. CNS -- invasion, multiplication, intraneural spread, motor neurons destroyed --> paralysis. / makes SINGLE polyprotein that is self cleaved into capsid proteins & non-structural proteins. Proteolytic processing --> effect host cell by inhibiting translation (--> cell death)
Enterovirus dx? (4 ways)
1. Virus isolation -- stool specifimens and throat washings, CSF, specific, sensitive, time consuming (cell culture); 2. Serologic -- faster. 4 fold or greater rise in titier (acute vs. convalescent), neutralization (type specific); 3. PCR (multiplex); 4. Virochip -- all known viral sequences imprinted on a glass slide. sample DNA and/or RNA is fluorescently tagged and hybridized to slide. does NOT require laboratory growth of virus.
Poliovirus -- 2 types of vaccine
1. Inactivated virus vaccine (SALK) -- cannot undergo genetic mutation to increased virulence, safe for immunocompromised people; 2. Life attenuated virus vaccine (SABIN) -- drop on tongue (oral vaccine), induces both systemic and secretory immunity. induces herd immunity (as it grows, viruses are shed --> vaccination of other people as well)
Gastroenteritis -- viruses that most commonly cause this?
Rotavirus, Caliciviruses (norovirus), Enteric adenoviruses, Astroviruses. (sometimes coronavirus, enterovirus, influenza virus)
Enterovirus 70 causes?
Acute hemorrhagic conjunctivitis
Enterovirus 71 causes?
Hand, foot, and mouth dz
Rotavirus -- pathogenesis
- Attachment to and infxn of enterocyte in villous epi of SI. - virus causes death of cells at villi tips (cell destruction and altered cell fn results in loss of permeability of intestine). - NSP4 (enterotoxin) released from infected cells: Intracellular NSP4 -- increase intracellular Ca levels by PLC-independent pathway, disrupts tight jn; Extracellular NSP4 -- (from previously infxted cell) signaling cascade through PLC and Inositol phosphatase (IP3) --> release of Ca --> could lead to activation of enteric nerves (Cl- secretion induction)
Rotavirus -- immunity/epidemiology
Musocal, humoral immunity is key. Early IgM in duodenal fluid and serum. IgA & IgG in 1-4 mths. IgA declines and susceptibility returns but repeat infxn shows less severe dz. Cell-mediated immunity NOT play role. Not clear yet if Rotavirus is systemic dz (although evidence shows that rotavirus infxn results in viremia). / Virus shed at high levels in feces. Need only <100 for dz. 2-5 day lasting. Late FALL to SPRING. NO pandemics. wave phenomena (strains move from west to east, south to north)
Rotavirus -- structure
Genome (11 ds RNA segments encoding 12 genes), NO envelope, 3 layered capsid -- 1st layer (VP2), 2nd layer (VP6 - subgroup antigen A-E), 3rd layer (neutralization antigen VP4 (P serotype 28) & VP7 (G serotype 19), multiple antigenic group (VP6 A-E), great diversity of antigenicity (multiple serotypes), co-infection can lead to reassortment of segments, Group A is MC cause of human dz, mutation rate 1000X higher than DNA viruses (due to RNA polymerase)
Rotavirus -- replication
Trypsin in GI tract activates virus --> removal of outer capsid (uncoating) --> enzymatically active core particle synthesizes mRNA --> some goes to translation and other make -ssRNA (with +ssRNA makes dsRNA --> viroplasm dsRNA + capsid) --> final virus assembly in ER --> release.
Rotavirus vaccines -- 1. Rotashield; 2. RotaTeq; 3. Rotarix
1. Rotashield -- withdrawn in 1999 due to intussusception (telescoping of intestine). Live attenuated reassortment virus from monkey. contained 10 genes from rhesus monkey rotavirus reassorted with each of 4 major human viral protein 7 (VP7). Trials showed >50% protection from diarrhea, 100% protection from severe dz.; 2. RotaTeq -- approved in 2006. Live attenuated vaccine, human-bovine reassortant, mixture of 5 diff virus types. Given 3 times orally b/w 2,4,6 months; 3. Rotarix -- approved in 2008. live attenuated single human strain based on most prevalent circulating strain globally. given 2 times orally at about 2,4 months.
Considerations for Vaccines (virus) -- related to Rotavirus vaccines
vaccine related intussception, prossible reversion to virulent strain (mutation), Viremia (side effects), shedding of virus by vaccine recipients, immunosuppressed children,
Virus responsible for >90% of food-related outbreaks of gastroenteritis in US?
Norovirus
Norovirus -- epidemiology, pathogenesis
Major cause of acute gastroenteritis in school-aged children and adults. >90% of food-related outbreaks of gastroenteritis in the US. Very short incubation time (8hrd - 2 days). 2-3 days of diarrhea with vomiting. Virus shed in stool. Transmission -- fecal-oral or vomitus (aerosol), food-borne or person to person. Pathology -- loss of epithelium, inflammation of mucosa, villus shortening, poor absorption of water and nutrients. (difficult to study as hard to grow in culture). Highly infectious (need <100 organisms). Great genetic diversity (213 strains of Norovirus detected)
Norovirus -- structure
Caliciviridae family. Nonenveloped. +ssRNA. 5 genogroups recognized -- based on nucleotide sequence --> "genotypes" (sequence homology). Genome organization -- Non-structural protein (include viral protease and viral RNA-dependent RNA polymerase), VP1 capsid (responsible for genomic variation), VP2
Norovirus -- ptn response?
1. 20% population -- resistant to Norovirus. Lack HBGA (histo-blood group antigen) receptors. no virus shedding, no serum or salivary AB; 2. 80% pop i) 45% infected -- virus shedding, symptomatic dz, Late (>5 days) serum IgG, Late musocal IgA; ii) 35% protected -- no virus shedding, no symptomatic dz, no serum IgG, early (<5 days) IgA (aren't sure yet how this works)
Astrovirus
One of the leading causes of acute viral gastroenteritis in INFANTS. Clinically important pathogen in the ELDERLY and IMMUNOCOMPROMISED. +ssRNA. Spherical virion with small spikes, NO envelop, star-like appearance. Can replicate in human colon carcinoma cell line. Infect many animal species. > 8 serotypes. Incubation 1-4 days. illness lasts 4 days (diarrhea, vomiting, abdominal distention, mild dehydration. Less severe than Rotavirus. Infxn limited to intestinal epithelial cells. Immunity to infxn is probalby short-term and dependent on IgA (exact mechanism of immune protection unclear)
Adenovirus
Latent virus in adenoids and tonsils. 51 serotypes (each assoc with diff dz spectrum). Cross-reactivity - family common antigen - reduces infxn with other types and re-infxn is RARE. dsDNA NOT enveloped. transmission -- focal/oral route or respiratory. Frequently causes unapparent respiratory infxn -- latency. Path -- Virus attaches to apical surface. Virus shet into intestinal lumen. excess virus penton spike fiber released from cells disrupts adhesion junctions leading to water and virus out from lumen). Dz -- Gastrointestinal in children, other dz include respiratory, hepatitis, genitourinary, ocular, encephalitis, systemic. Dz more severe in IMMUNOSUPPRESSED, esp pneumonia and GI dz. Enteric adnovirus infxn -- incubation 3-10 days, diarrhea lasts 6-9 days, may have vomiting and fever preceding diarrhea. children > adults. causes 5-15% of gastroenteritis in young children.
Gastrointestinal viruses -- Dx, prevention, tx
Dx -- RT-PCR with specific primers, Immunoassays to detect viral antigens, Immunoelectron microscopy and standard EM; Prevention & Tx -- Hydration and maintenance of electrolyte balance. NO specific antiviral agents. Vaccine for Rota virus.
Virus causing gastroenteritis in infants, elderly, immunocompromised?
Astrovirus
Orthomyxovirus -- classification (types vs. subtypes), Antigenic drift vs. shift
Types -- Influenza virus A, B, C (based on matrix and nucleoprotein antigens); Subtypes -- H1N1, H2N2, H3N2 (A only. based on HA and NA)/ antigenic drift -- mutations in HA and NA. antigenic shift -- reassortment b/w human and animal strain.
Influenza virus -- Pathogenesis
Influenza = acute respiratory dz. Virus infects ciliated epithelial cells lining upper respiratory tract, trachea, bronchi. Virus passes thorugh respiratory secretions via action of NA on mucoproteins. Virus replication leads to destruction of respiratory epithelium. Cell damage also due to virus activated CTL. Viremia is NOT a major role in pathogenesis.
Influenza virus -- clinical features
fever, chills, generalized aching (particularly muscular), headache, exhaustion, anorexia, sore throat, and NONproductive cough. Normally self-limited dz lasting 3-7 days, more severe in young adn old ptns. Secondary bacterial pneomonias are major cause of death -- Staph. Aureus, H.influenza, beta-hemolytic Strep, Strep pneumonia. Fatal primary influenza without bacterial invasion is rare but does account for the unusual deaths with primary influenza. Extrapulmonary lesions -- encephalitis, Reye syndrome (encephalopathy and fatty liver)
Reye's syndrome
Encephalopathy and fatty liver. related to Influenza virus.
Influenza virus -- replication
bind to sialic acid--containing receptors --> influenza endocytosed and fuses with vesicle membrane. Transcription and replication happens in nucleus. --> viral proteins are synthesized, helical nucleocapsid segments form adn associate with M1 protein -- lined membranes containing M2 and the HA, NA glycoproteins. --> Virus buds from plasma membrane with 8-11 nucleocapsid segments.
Influenza -- prevention and control: Immunization & Chemotherapy
Immunization -- Formalin inactivated (mixture of prevalent antigenic types), subunit vaccines (HA and NA), attenuated infectious viruses (intranasal administration), recombinant DNA vaccine, genetic reassortment, reverse genetics; Chemotherapy -- amantadine and rimantadine (inhibit uncoating by blocking M2 protein), ribavirin (inhibits synthesis of viral RNA), Zanamivir (relenza) and Oseltamivir (Tamiflu) NA inhibitors.
Influenza virus -- Amantading and rimantadine, Ribavirin, Zanamivir, Oseltamivir
Chemotherapy -- amantadine and rimantadine (inhibit uncoating by blocking M2 protein), ribavirin (inhibits synthesis of viral RNA), Zanamivir (relenza) and Oseltamivir (Tamiflu) NA inhibitors.
Rhinovirus - Sx, pathogenesis, Prevention & control
Picornavirus (similar replication and structure to Poliovirus), cause 50% of common cold. 115 serotypes. Sx -- headache, cough, sore throat, mucopurulent nasal discharge "runny nose"; Path -- due to inflammatory response, infected cells in the nose release bradykinin and histamine; temperature sensative -- likes 33 > 37. Secretory IgA most important in limiting re-infxn. Transmission by respiratory secretions -- directly from individual to individual, via fomites. Prevention & control -- No effective prevention and control to date. Experimental -- Viral protease inhibitors (Ruprintrivir), WIN compounds (block uncoating by inserting in virus surface pore - Pleconaril), others (IFN-alpha to induce antiviral resistance, Soluble ICAM-1 to compete for attachment).
What is the the cause of >50% of common cold? second most prevalant cause (10-15%)?
Rhinovirus, Coronavirus
What is important related to Rhinovirus in limiting re-infxn?
Secretory IgA
Coronaviruses - Sx, vaccine
Second most prevalent cause of common cold (10-15%). SARS sx -- cough, sore throat, SOB and difficulty breathing due to pneumonia, fever > 38, low white cell count. Sx appear 3-7 days after exposure. Dz limited to URT, infects epithelial cells (optimal temperature for growth 33-35). Infxn occur winter to early spring. Re-infxn common despite pre-existing serum AB, NO vaccine available --> control outbreak with containment
Coronavirus -- SARS
Fatality rate among people with illness is 15%. Transmission -- face-to-face contact (virus in respiratory secretions and feces). NO efficacious therapy available. NOT a recombination or mutation of known human coronavirus. Related to viruses in civets, raccoon dog, chinese horseshoe bats. Structure -- "sun-like". +ssRNA. lipid bilayer (enveloped). Peplomeric glycoprotein E2 (mediate cellualr attch & fusion), Transmembrane glycoprotein E1, Nucleoprotein N; Antiviral target -- uncoating, eliminate protease, assembly of membr-bound polymerase complex, transcription/replication, ER budding, exocytosis.
paramyxovirus -- structure
-ssRNA, F (fusion protein virus entry), HN (hemagglutinin virus attchmt, Neuroasminidase virus release -- NOT in RSV), RNP
Parainfluenza virus
Paramyxovirus family. Transmitted by respiratory secretions. Incubation 2-4 days. usually fall-winter. Common nosocomial infxn. Infect epithelial cells in URT, viremia rare. Types 1,2,3 -- cause RT dz ranging from mild common colds to bronchiolitis and/or pneumonia. Type 4 -- mild dz. Lower respiratory complications in infants and young children -- CROUP (subglottal swelling may close airway). IgA (against HN) in nasal secretions important in protection but are short lived. Dz more seere in children with T-cell deficiencies. NO vaccine available.
RSV - location of effect, repeated infxn?
RSV infxn rate -- 70% in 1st year with peak incidence b/w 2-4 months. Most children -- mild URT infxn. 20-30% of RSV-infected infants -- LRT involvement (Most common cause of LRT infxn-related hospitalization in children < 1 yr). RSV causes repeat infxn throughout life with serious complications occuring most often in elderly and immunecompromised.
What is the most common cause of lower respiratory tract infxn-related hospitalization of children < 1yr of age? (3%)
RSV
RSV - immunity, modulation of immune response by RSV
RSV in Lower airways -- severe LRT infxn early and late in life and repeat infxn with same or different strains of RSV common. / RSV in Upper aiways -- Local, transitory expression of secretory IgA mediates resistant. Longer-lived humoral immunity is conferred by IgM and esp. neutralizing IgG. AB production usually low in children. Infants -- the level of passively acquired maternal AB correlates with protection against serious LRT infxn. T-cell response controls established RSV infxn preventing severe RSV dz and limiting virus shedding. / RSV may modulate aspects of immune response to promote virus replication -- i) Membrane-bound and soluble RSV G protein can interact with specific chemokine receptors and inhibit responses mediated by NK cells, Th1-type cells and CTL. ii) RSV NS2 protein is an IFN antagonist (deletion of NS2 gene attenuates virus)
RSV -- dz mechanism, histology
Localized infxn of respiratory tract. does NOT cause viremia or systemic spread. Pneumonia - results from cytopathologic spread of virus. Bronchiolitis - result of host immune response. Narrow airways of young children - obstructed by virus induced pathologic effects. Maternal AB does NOT protect infants from infxn but help prevent severe dz. Natural infxn does NOT prevent re-infxn. Improper vaccination has increased severity of dz. Typical giant cell with a round, pink intracytoplasmic inclusin. Syncytia not always present
RSV -- dz severity
Type of CD4+ T cell response to RSV infxn determines dz severity. 1. common adult response: Th1 --> IFN-gamma --> (i) Macrophage, NK cells, Cell-mediated immunity --> Antigen presentation, Cytolysis, Antiviral cytokines, Virus clearance / (ii) B cells --> IgG1, IgG2a; 2. Often in infants: Th2 --> (i) IgG4, IgG1, IgE --> Mast cell activation --> Prostaglandin D2, Histamine --> wheezing / (ii) IL-4 --> mast cell activation / (iii) IL-5 --> eosinophilia --> wheezing
Function of RSV NS2 protein? what about Membrane-bound soluble RSV G protein?
RSV N2 protein -- IFN antagonist; RSV G protein -- interact w/ specific chemokine receptors and inhibit responses mediated by NK cells, Th1-type cells, and CTL.
RSV- epidemiology
very contagious, almost all children have been infected by 2 yrs. Transmitted on hands, fomites, and by respiratory routes. RSV infxn almost always occur during winter in termperate climates.
RSV - control of infxn - Vaccines, AB prophylaxis, Antivirals
Vaccines -- inactivated vaccines (bad, poor results. increased dz severity upon natural infxn), live attenuated vaccine (no increase in dz severity with natural infxn but poor long-term protection; potential for virulence), Deletion of NS2 gene (genetically stable but OVERattenuated); AB prophylaxis -- 1st developed (polyclonal human AB prepration REspiGam (RSV syncytial virus immune globulin), Palivixumab (Synagis) (humanized monoclonal AB against F protein), Motavizumab (higher potency variant derived from Palivizumab; Antivirals -- aerosolized ribavirin (FDA approved, inhibits viral RNA synthesis), RSV604 (novel benzodiazepine with anti-RSV activity involving the viral nucleocapsid protein), Small interfering RNAs (siRNAs) directed against the mRNA encoding the RSV nucleoprotein, small molecule fusion inhibitors.
Palivizumab (Synagis)
RSV -- humanized monoclonal AB against F (fusion protein)
Motavizumab (MEDI-524)
RSV -- higher potency variant derived from Palivizumab
Aerosolized ribavirin
RSV antiviral -- inhibits viral RNA synthesis
RSV604
RNA antiviral -- novel benzodiazepine with anti-RSV activity involving viral nucleocapsid protein
small interfering RNAs for RSV
RNA antiviral -- against mRNA encoding the RSV nucleoprotein
Metapneumovirus
Paramyxovirus family. Newly identified in 2001. Acute respiratory illness in children and adults. Clinical spectrum of dz similiar to RSV with most severe dz in infants, elderly, and immunocompromised. URT infxn, bronchitis, wheezing, pneumonia. By 5 yrs almost all children are seropositive. ID by RT-PCR.
Viruses that follow Respiratory transmission --> Replication in URT --> Upper and sometimes lower respiratory infxn and Dz
Rhinovirus, Coronavirus, Parainfluenza virus, RSV, Metapneumonitis, Adenovirus (sometimes)
Viruses that follow Respiratory transmission --> Replication in URT --> VIREMIA --> Target organs & sx
Measles, Mumps, Rubella, Hendra & Nipah (?), Parvovirus B19, Adenovirus (sometimes)
Natural infxn usually protects against re-infxn with same strain for most respiratory viruses. What is an exception?
RSV causing severe lower respiratory tract infxn.
Why are immunizations against Measles, Mumps, and Rubella so effective? (3 reasons)
1. Each virus has only ONE antigenic type; 2. Each virus has a SYSTEMIC REPLICATION phase prior to infecting target organ where symptoms develop - AB developed as a result of immunization can limit or block virus at this stage; 3. Humans are the ONLY known host
Measles -- Pathogenesis
Paramyxovirus family. Inoculation of RT --> Local replication in RT --> Lymphatic spread --> Viremia --> wide dissemination --> Conjunctivae, RT, UT, Small blood vessels, Lymphatic sys, CNS --> Virus-infected cells + immune T cells --> Rash --> Recovery (lifelong immunity), Rare outcomes [Postinfectious encephalitis (immunopathologic etiology), Subacute sclerosing panencephalitis (defective measles virus infxn of CNS), No resolution of acute infxn caused by defective CMI (frequently fatal outcome)]
MMR vaccine -- effectiveness, how it works, when it should be given
Live, attenuated viruses given as combination. 12-15 months and 4-6 yrs. Induce strong, long-lasting AB response. Vaccine-induced immunity blocks virus during systemic stage and prevents infxn of target organs. Effective vaccine, just need to give to everyone
Timing of Vaccine -- 1. MMR; 2. Rotavirus - RotaTeq, Rotarix
1. 12-15 months & 4-6 yrs. 2. i) RotaTeq -- approved in 2006. Live attenuated vaccine, human-bovine reassortant, mixture of 5 diff virus types. Given 3 times orally b/w 2,4,6 months; ii) Rotarix -- approved in 2008. live attenuated single human strain based on most prevalent circulating strain globally. given 2 times orally at about 2,4 months.
Hendra & Nipah virus
Henipavirus family. emerging respiratory viruses with HIGH mortality rate. Bats --> pigs --> humans. Hendra (Australia) and Nipah (Asia)
Adenovirus -- structure, sx, path, tx/prevention
dsDNA, NOT enveloped, icosahedral capsid with penton spikes. 51 human serotypes (each associated with different dz spectrum), wide spectrum of Dz -- resp infxn (pharyngitis --> CAN lead to SYSTEMIC infxn - viremia), CONJUNCTIVITIS (pink eye), GI infxn, hemorrhagic cystitis (inflm of urinary bladder), [hepatitis, meningoencephalitis]. Respiratory tract -- can cause destructive productive infxn, persistent infxn with virus shedding, or LATENT VIRUS IN ADENOIDS and TONSILS. Systemic infxn in immunocompromised ptns. Cross reactivity -- family common antigen, reduces infxn with other types and re-infxn is rare. Stimulates cells to enter S PHASE (enabling DNA synthesis): Early (E1) genes; Late genes -- E1A binds Rb, E1B binds p53 (viral proteins bind to cellular growth suppressor proteins). Antiviral therapy -- CIDOFOVIR ("VISTIDE"). used in severe infxns with adenovirus and some other DNA viruses. Adenovirus infxn in bone marrow transplant ptns. acts as a VIRAL DNA POLYMERASE INHIBITOR
Cidofovir - "Vistide"
Adenovirus antiviral therapy. viral DNA polymerase inhibitor.
Parvovirus B19 -- structure, pathogenesis/spread
ssDNA, Icosahedral, NON-enveloped, replicates in NUCLEUS, dependent on host DNA replication fns (use cellular DNA polymerase to replicate). Viremia -- infects actively replicating RBC progenitors in bone marrow. receptor is blood group P antigen (globoside) expressed on mature erythrocytes, erythoid progenitors, megakaryocytes, endothelial cells, placenta, fetal liver, and fetal heart. Spread in body -- 1. virus in URT --> local replication --> Viremia --> i) viral replication in URT; ii) Rash and arthralgia (Erythema infectiosum or fifth dz). 2. Virus in URT --> viral replication in erythroid precursor cells in bone marrow --> i) viremia; ii) normal host (slight drop in Hb level); iii) host with chronic hemolytic anemia (life-threatenig aplastic crisis due to destruction of RBC). When transmitted to fetus -- can cause still births, generalized edema (fetal hydrops), anemia, CHF. Associated with fetal death, NOT congenital abnormalities.
Bocavirus
Newly discovered Parvovirus responsible for respiratory and GI tract infxn.
Parvovirus B19 -- time course of infxn
Incubation -- 6 days --> Lytic infection phase (virus in throat, viremia, nonspecific fluelike symptoms - 5 14 days --> Noninfectious immunologic phase (Virus specific IgG AB present, Rash/arthralgia - 2-4 wks). Virus very difficult to isolate from any site after the lytic infection phase (after about 2 weeks)
Parvovirus B19 -- clinical features
Clinically inapparant infxn -- usually. Clinically apparent infxn -- Erythema infectiosum (fifth dz) -- 4-14 days incubation, bright red cheeks (slapped cheek rash), maculopapular rash, circulating immune complexs, primarily IgM with virions, then IgG, complexes do NOT fix complement, but cause rash, arthralgia, and arthritis; Epidemiology -- respiratory transmission, vertical
Hep A -- structure, transmission
Picornavirus -- +ssRNA, Icosahedral, Non-enveloped, CAPSID STABLE (to acid, drying, detergents). enters cells via receptor that is enriched in liver. mRNa translated into ONE polyprotein which is cleaved to form mature products. UNLIKE other picornavirus, NOT cytolytic but is SHED from cells --> NO GOOD TISSUE CULTURE SYSTEM FOR HEP A; SINGLE serotype worldwide. Acute dz and asymptomatic infxn. NO CHRONIC INFXN. Transmission -- fecal oral route, spread by contaminated food, water, raw shelfish, poor hygeine, MC spread -- food handlers, daycare workers, children. Virus is steadly released from infxed hepatocytes. NK and cytotoxic T cells eliminate infxted cells; AB response also assists in viral clearance. Liver pathology is most likely IMMUNOPATHOLOGY (NOT cells killing them)
Hep A -- Clinical features, Clinical course. Vaccine
Incubation period -- Avg 30 days (range 15-50days), Jaundice by age group (<6 yrs - <10%, 6-14 yrs - 40-50%, > 14yrs - 70-80%). Rare complications -- fulminant hepatitis, Cholestatis hepatitis, Relaping hepatitis; Clinical course -- Prodrome (1 month) --> Highest viral activity (2 wks - 1 mth) --> Recovery (about > 2 months after infxn). Inactivated Hep A vaccines -- Cell culture adapted virus grown in human fibroblasts, purified product inactivated with formalin, adsorbed to aluminum hydroxide adjuvant. recommended for infants, people working in or traveling to areas with high incidence of HAV, with chronic liver dz, working with HAV.
Hep E Virus
Enteric virus. Calicivirus family. +ssRNA, icosahedral. Epidemiology -- most outbreaks associated with fecally contaimnated drinking water. minimal person-to-person transmission. Is NOT endemic in the U.S. (get from traveling)
Hep B Virus - structure, replication cycle, products, risk factors
Hepadnavirus (genotypes A-H), Circular DNA genome, partly dsDNA, Not uniform in shape. Chronic infxn more when YOUNG. Replication cycle -- Genome enters, DNA synthesis occurs to form fully ds DNA (in cytoplasm) --> Genome goes to nucleus, transcribed to mRNA --> mRNa translated in cytoplasm --> mRNa "reverse-transcribed" to ssDNA, DNA made partially ds --> DNA encapsidated into new virion (on ER) --> Virions & sub-viral particles of sAg released. DNA can integrate into cytoplasm and remain in cell. NO GOOD TISSUE CULTURE SYSTEM FOR HEP B. HBV infected cells produce (after 2 months) Infectious Virus & Non-infectious HbsAg particles (Antigen w/o DNA - immunogenic but NOT infectious. Foundation & concept for vaccine; send as decoy (good) BUT exposing too much to the body). RIsk factors -- Heterosexual (41%), Unknown (30%), Injecting drug use (15%), Homosexual activity (9%). Transmission -- Blood, sex, IV drug use, neonatal. Need good immune system to clear.
What are the two products of Hep B virus infected host cells (that relates to dz?)
1. Infectious virus; 2. Non-inectious HbsAg particles -- immune complex dz.
Hep B virus -- clinical outcomes
(in adults) 90% resolution; 1% fulminant hepatitis (w/ Hep D); 9% HBsAg for > 6 months --> 50% resolution, Asymptomatic carrier state, Chronic persistant hepatitis, Chronic active hepatitis --> Cirrhosis, Extrahepatic dz (PAN, Glomerulonephritis), Hepatic cell carcinoma (rare result of Hep B but Hep B is the major cause of Hepatic cell carcinoma); Immune control, and the presence of HDV can influence the outcome of HBV infxn -- 1. Effective cell-mediated immune response: kills HBV in liver --> acute dz (sx - jaundice, release of enzymes) --> resolution; 2. Limited cell-mediated immune response --> Chronic dz (mild sx) --> i) with delta agent --> Fulminant hepatitis, (ii) primary hepatocellular carcinoma, (iii) Cirrhosis
Hep D (delta) virus
"Viroid" - can only grow in Hep B infected cells. Small RNA -copied by host RNA polymerase II, catalytically active "ribozyme" that processes itself. Encodes ONE antigen, becomes packaged in Hepatitis B sAg. Clinical -- Coinfection (severe ACUTE dz, low risk of chronic infxn). Superinfxn (subsequent to HBV infxn. Usually develop chronic HDV infxn. high risk of severe CHRONIC liver dz)
Why does chronic HBV infxn correlate with high incidence of HCC (hepatocellular carcinoma)?
1. INJURY TO LIVER causes sustained cell proliferation of cells that are usually quiescent, enabling genetic errors to accumulate. 2. INTEGRATION OF VIRLA DNA into host chromosomes (>85% of HBv-induced HCC) causes GENOMIC STABILITY and can lead to alterations in host gene expression. 3. VIRALLY-ENCODED X PROTEIN linked to signal transduction cascades that can be oncogenic. X DECREASES P53 ACTIVITY as well as affecting other key pathways. In "transgenic" mouse models of HBV oncogenesis, HCC is correlated with surface antigen expression (causes liver injury, hyperplasia, inflammation) and X expression.
HBV -- prevention and tx
Blood supply screened, Vaccination is key to prevent infxn of high-risk individuals and of infants. Subunit vaccine -- recombinant HBsAg produced in yeast (self assembles into immunogenic particles. Universal blood/body fluid precautions. Lifestyle precautions. Polymerase inhibitors, nucleoside analogs, IFN-alpha --> 7 licensed drugs (resistant viruses do appear). New approaches to silencing HBV expression during chronic infxn.
Hep C - general characteristics.
Most prevalent NANBH. Flavivirus --- +RNA, enveloped, 9Kb genome (10 proteins). Many quasi-species (error-prone RNA polymerase -- can't vaccinate). Encodes MULTIPLE IMMUNOMODULATORS enabling virus persistence (stealthy). liver damage primarily due to IMMUNOPATHOLOGY; VIRAL REPLICATION INDUCED ROBUST INNATE IMMUNE RESPONSE. High incidence of chronic and asypmtomatic infxn (allows apread through population -- chronic in adults which is opposite of Hep B). Assoc with increased incidence of hepatocellular carcinoma (delayed onset).
Hep C - Progress in studying Hep C in tissue culture?
Full DNA genome introduced into cells directs full viral life cycle w/ production of infectious virus --> greatly facilitating analysis of the life cycle adn enable screening for antiviral therapies; No standard tissue culture sys for studying viral infxn. Previously developed - "replicon" system for introducing partial DNA version of genome -- enabled analysis of replication but did NOT produce virus.
Hep C -- Clinical outcomes, therapies
15% recovery, 85% persistent infxn --> Chronic hepatitis --> 6% liver failure, 20% Cirrhosis, 4% Hepatocellular CA. Pegylated Interferon (addition of polyethylene glycole that enhances half life), Ribavirin (nucloside analog, Pol inhibitor) -- in combination, reasonably effective therapy but not for all viral genotypes. Currently in devo -- Protease inhibitors, Non-nucleoside polymerase inhibitors, Therapies aimed at inhibition of NS5A (nonstructural protein essential for replication, key immunomodulator)
NS5A related to what virus? NS3 related to? NS2 related to?
Hep C, Hep C, RSV
Hep C -- sources of infxn
IVD (60%), Sexual (15%), Transfusion (10%), Unknown (10%)
Why does Chronic HCV infxn lead to high incidence of Hepatocellular CA?
1. HCV CORE PROTEIN -- i) interacts with, and regulates, many cellular tumor suppressors (p53, Rb) and signal transduction pathways involved in proliferation; ii) induces STEATOSIS (lipid accumulation) leading to "fatty acid spiral", oxidative stress and increased cell proliferation. Steatosis accelerates development of HCC. (transgenic mice expressing HCV core protein develope HCC). 2. HCV ENVELOPE PROTEIN (E2) -- inhibits NK cells and can activate cell proliferation pathways; 3. NS# -- can enhance cell growth and block the action of the p53 tumor suppressor; 4. NS5A -- can enhance cells growth, prevent action of p53
HCV -- new advances in understanding HCV/host interactions (2)
1. miRNA-122 -- small processed RNAs that regulate other mRNAs in a sequence-specific manner. Most abundant mRNA in liver, binds to 2 sites in 5'UTR of HCV genome --> enhancing tranlation and/or replication. SPC3649 targets miR-122 and leads to its depletion; 2. IL28b gene -- GWAS analysis used to identify genetic polymorphisms that might define i) which ptns clear HCV infxn vs. those who develop chronic illness, ii) which ptn response to tx with pegylated IFN and which do not. IL28b gene -- encodes ANTIVIRAL CYTOKINE IFN-gamma. polymorphism within IL28b gene has strong impact on devo of chronic infxn and on responsiveness to IFN therapy.
SPC 3649
targets miR-122 in HCV related infxn
Rabies - structure
Lyssavirus – included Rabies, Vesiculovirus – vasicular stomatitis virus of horses, cattle, and pigs; can cause flu-like disease in lab workers;
-ssRNA, Rod or bullet shaped, enveloped Envelope (G) – bind cell via several receptors
o Ganglioside and CD56 in neurons, nicotinic acetylcholine receptor in muscle
o Target of neutralizing Ab
 Nucleocapsid - Negative ssRNA with protein is helically coiled
 Matrix protein (M) under envelope
 RNA genome associated with – Nucleocapsid (N) coats RNA, NS and L proteins form RNA Pol.
 Replicate in cytoplasm
Rabies -- replication
Replication
 Envelope binds via several receptors
 Virus is endocytosed, envelope fuses with low pH endosomal membranes to release nucleoprotein
 RNA-dependent RNA polymerase initiates transcription in 3’ leader of – RNA, adds a cap, and “stutters” to make 5 polyadenylated mRNAs by reinitiation One single RNA strand --> encodes multiple proteins
 Buildup of N protein causes polymerase to make full length positive RNA – serves as template for genome transcription by the same polymerase
 nucleocapsids (RNA, N, NS, L) form in cytoplasm and associates with M
 G protein inserted in membrane/associates with M
 Nucleocapsid, G, M proteins associate and cores bud from cell
 Rhabdovirus budding kills the cell – not true for rabies
Rabies -- epidemiology , transmission
Epidemiology
 U.S. – fewer than 6 human cases/year
 Imported cases (tourist exposed outside of U.S., usually by dog bites)
 Worldwide – increased, >55,000 deaths/year, mostly from dogs
o Transmission
 infected saliva via entry through wound or skin abrasion
 aerosolized if high enough concentration (caves)
 transmitted through infected cornea transplants or organ transplants
Rabies -- path, immunity
Pathogenesis
 replicates in muscle or connective tissue during incubation period (could be months)
 enters peripheral nerves at muscle (prodrome phase), carried to CNS intervention before spread to CNS is effective. move 8-20 mm/day
 CNS – virus replicates in brain, spreads via neurons to skin, cornea, salivary glands, other organs. No detectable viremia
 Little pathology observed – nerve cell destruction, encephalitis, Negri bodies may be seen
o Immunity
 1 viral serotype, several strains – distinguished by monoclonal antibodies (Vaccine of Pasteur -- serial passage in rabbit brain in lab yields an attenuated or fixed strain - short incubation period (1 wk) and no inclusion)
 Immune response occurs, insufficient to prevent disease
 G glycoprotein – antibodies are neutralizing, Hemagglutination inhibiting (lab test)
Rabies -- Sx
Symptoms
 Incubation period – asymptomatic – 3-8 weeks Time depends on dose and location of bite Low titer, no Ab, virus in muscle
 Prodrome – 2-10 days Nervousness, headache, anxiety, pain at bite site, fever, nausea Low titer, virus in CNS and brain, no Ab
 Acute Neurological phase – 2-7 days High virus titer in brain and elsewhere, Ab present in serum and CNS Furious or fulminant – classic rabies
o Bizarre behavior, hallucinations, seizures, hydrophobia, violent spasms of respiratory muscles triggered by speaking or drinking water  sight, sound, or mention of water
o Gives way to paralysis, then either coma or sudden fatal cardiorespiratory arrest Paralytic or “dumb” rabies – 20%; ascending flaccid paralysis leads to fatal paralysis or respiratory muscles
 Rabies is almost always fatal once symptoms appear
Rabies -- Dx & ID
Diagnosis & I.D.
 High discrimination – neurological symptoms in person known to be bitten
 Confirmation Viral antigens in CNS or skin – direct immunofluorescence (dFA) with N antibodies RT-PCR, ELISA (detection of antibody), Presence of Negri bodies (replication centers)
o Prevention and Treatment
 Immunization of domestic animals and high risk individuals
 Post-exposure prophylaxis – for both patient and many individuals who came in contact with patient
 Local wound treatment (soap & water) + PEP --> most always abort infxn
 Passive immunization – immune globulins (of human or equine rabies - HRIG/ERIG) introduced to wound area --> provide AB until immunization becomes effective
 Active immunization – killed virus – 5 doses at 0, 3, 7, 14, 28 days post-exposure
Prions -- structure, path, dx, tx
Structure
o Normal protein encoded by cellular gene, PrPC on chromosome 20, very high in CJD
o Found on cell surface & expressed in many tissues
o Implicated role in synaptic function or neuronal maintenance/survival? / Pathogenesis
o Normal α-helical protein  insoluble PrPSC (β-sheet) that aggregates (into a highly insoluble form, accounts for resistance to inactivation --> Infectivity thought to be associated with conversion of nornal alpha-helical protein to insoluble beta-sheet form. PrPSC is infectious BUT it doesn't replicate
o Prion aggregates taken up by neurons, difficult to degrade & long-lasting
o Spongiform appearance from vacuoles, compromised function;
o sometimes amyloid plaques and proliferation and hypertrophy of astrocytes
o long incubation period – slow infection (months to decades)
o Chronic progressive pathology – once symptoms become evident, death usually within a year
Diagnosis & I.D.
o No methods to directly detect prions
o Diagnosis made on clinical grounds and upon brain tissue histology Prevention and Treatment
o No treatments
o Careful disinfection of medical instruments is necessary
Scrapie, Kuru, Bovine encephalopathy (BSE), CJD
“Scrapie”
o Sheep, goats, mink
o Neurological problems cause animals to scrape against fence posts
o Brain and lymph tissue is infectious /Bovine spongiform encephalopathy (BSE) – “Mad Cow” Disease
o Caused by use of sheep tissue in food supplements / Kuru (to ‘shiver’)
o Spread by ritualistic cannibalism
o Ataxia, shivering-like tremor
o Progresses towards complete motor incapacity and death within 1 year of onset /Creutzfeldt-Jakob Disease
o Epidemiology
 1 case/million in U.S. and Europe – most common human prion disease
 Sporadic – older individuals (60-65) – natural route unknown, spontaneous change in prion protein
 Contaminated BSE beef – occurs in young people, similar but atypical symptoms
 5-10% of cases are familial, dominantly inherited forms
o Transmission – growth hormone injection, corneal transplant, electrode implants
o Symptoms – progressive dementia leading to ataxia, paralysis, wasting, death (usually by pneumonia) within 6 months of onset
Prion-only hypothesis -- how is it in infectious protein?
Evidence that Prions are Protein only -- PrPsv and infectivity copurify. unusual properties of PrPsc mimic prions. Levels of PrPsc are proportional to prion titers. PrPsc accumulation always linked to dz. Overexpression PrPc accelerates PrPsc formation and shortens incubation time; Transgenic mice expressing WT and PrPsc get dz. PrPc knowckout mice are resistant to infxn. No normal protein present to convert. Yeast have similar proteins (a good model to study conversion mechanism)
Human Herpes viruses -- by classes (3)
Alpha (HHV-1, 2, 3) -- short replication cycle, latent primary in sensory ganglia, Broader host range; Beta (HHV 5, 6A, 6B, 7) -- longer replication cycle, latency in secretory glands, lympho-reticular system, kidney, host range limited; Gamma (HHV 4,8) -- slow replication, latency in lymphocytes and myeloid cells, host range limited
Herpesvirus -- general structure, defining characteristics
o Structure
 Genome – large linear dsDNA
 Enveloped, icosahedral, replicate in the nucleus
 Enveloped viruses are labile in environment: infectious virions survive up to 2 hours on skin, 4 hours on plastic surfaces
o Defining Characteristics
 Encode collection of enzymes involved in nucleotide metabolism (thymidine kinase),
DNA synthesis (DNA Pol.), protein kinase
 Synthesis of viral DNA and capsid assembly in nucleus
 Remaining virion put together in cytoplasm
 Two life cycles – lytic replication and latency
 Only viruses that acquire envelopes by budding from nuclear membrane
HSV-1 & HSV-2 -- replication
Replication
 Lytic infection: Binding and fusion -- Transport of DNA to nucleus -- Viral vhs degrades host mRNA -- VP16 (viral transcription factor) localizes to nucleus to initiate viral gene transcription; Viral DNA circularizes -- HSV α-genes transcribed by host RNA Polymerase II  some α-genes transactivate β-genes (β-genes – required for viral DNA synthesis)  Viral DNA synthesis triggers expression of gamma-viral genes (gamma-gene products are structural components of virion) -- viral DNA packaged into capsid  buds through host membrane to form mature virion
 Latent Infection: Circular viral DNA associates with host nucleosome; maintained as episome (looks like an extra chromsome) -- Most lytic genes are transcriptionally repressed through viral chromatin-associated histone code -- Occasional reactivation for life of host (physiological triggers  immune system alterations) / Herpesvirus is FOREVER -- immune sys clears replicating virus during acute infxn BUT herpesvirus maintain latency with occasional reactivation for the life of host. The SAME strain of herpesviruses persist within the same host. Reactivation may not destroy the original cell hosting the virus.
HSV-1 & HSV-2 -- Epidemiology, transmission, patho
Epidemiology
 HSV-1 = 60-70% are carriers; HSV-2 = 17% are carriers
 Humans are ONLY reservoir
o Transmission
 Person-to-person mucosal transmission
 Viral shedding – saliva; oro-facial, genital lesions and secritions
 HSV-1  more commonly shed from oral cavity
 HSV-2  more commonly shed from genital tract
o Pathogenesis
 Transmission to mucosa or abraded epithelium  robust lytic replication (primary infection) Certain cases, HSV may disseminate systemically
 Retrograde transport to sensory ganglia – latency HSV-1 – trigeminal ganglia; HSV-2 – sacral ganglia
 LATs (Latency Associated Transcripts) – viral mRNAs that are never translated into protein; fn to repress HSV gene expression
 Recurrent infection – antegrade transport of virions around site of inoculation, reinfxn of epi cells, lesion spread / Frequency of reactivation is HIGH -- in untreated HSV-2 positive individuals the chance of subclinical reactivation at a genital site 25% on any given day (but may be completely asymptomatic).
 Re-infection by a different strain of HSV is possible but uncommon (exogenous
re-infection)
HSV-1 & HSV-2 -- Sx, Dx, Tx
Symptoms
 Genital dz (both HSV-1 and HSV-2) - tx reduces shedding by 60-80% / Primary oral-facial infection – herpes gingivostomatitis or phayngitis
 Recurrent oral-facial infection – herpes labialis (coldsore)
 Neonatal herpes – inoculation during birth (most common) – Inoculation during pregnancy results in multiple birth defects Disseminated replication, CNS commonly affected, dz manifests within days of life (may NOT have skin lesions), High mortality even with acyclovir, Rx (survivors have high rate of neurological abnormalities). Tx of mother prior to birh decreases incidence
 Herpes encephalitis (rare)
 Herpes keratitis and conjunctivitis – leading cause of blindness in the U.S. Initial inoculation in eye; recurrent infections all manifest in eye
 Herpes gladiatorium – dermatitis of athletes in contact sports
 Herpes whitlow – hand dermatitis – problem in health care workers (gloves DON'T prevent transmission)
o Diagnosis & I.D.
 Vesicles at site of inoculation
 Viral culture, immunofluorescence with anti-HSVAg Antibodies, PCR assays
 Serology to determine infection status
o Prevention and Treatment
 No treatment modalities versus non-replicating (latent) infections. NO tx available to clear latent herpesvirus infxn. NO vaccines for HSV. Live-attenuated vaccine for Varixella zoster vaccine.
 Nucleoside analogs (acyclovir) – inhibit viral DNA synthesis, Suicide inhibitor, competes with dGTP (polymerase binds to ACV-PPP irreversibly --> ties up polymerase). Viral DNA polymerase recognizes ACV-PPP as dGTP analog and incorporates it BUT cellular DNA pol does not (cellular DNA pol has requires tighter fit) Relies on immune system to clear cells that lytically replicate herpes
Varicella Zoster -- epidemiology, transmission, Path
Epidemiology – Humans only reservoir
o Transmission
 Person-person contact, infected patient can spread disease before skin lesions appear
 Unique among HHVs: virus is AEROSOLIZED both from lesions and respiratory tract
o Pathogenesis
 Replication in T cells, epithelial, and endothelial cells
 Latency is maintained in sensory nerve ganglia
 Several viral gene products are actively transcribed and translated within latently infected neurons (unlike HSV)
 Primary infxn may involve CNS. Neurological abnormalities following treatment are uncommon (unlike HSV)
o Symptoms
 chickenpox Primary VZV infection; 10-21 day incubation period, Blisters (50-300, resolve without scare formation), itching, malaise, fever. Risks during primary infection:
o occurs in adulthood – secondary skin infections, pneumonia more common / ASPIRIN in COUNTERINDICATED as it predisposes to liver damage (Reye's syndrome)
o immunocompromised patients – infection can be disseminated and fatal Neonatal VZV – extremely rare, multiple developmental defects. / Antivirals (acyclovir), VZV immune globulin
 Herpes Zoster (Shingles) – reactivation of latent VZV from a SINGLE sensory ganglia. Controlled with antivirals (acyclovir). 1 million cases/year in US commonly >50 yrs age. Reactivation within trigeminal ganglia can lead to vision impairment. Postherpetic neuralgia – significant complication of Zoster
o Severe pain without vesicular lesion
o Pain can last for many months, antivirals have NO effect
o Can mimic appendicitis or heart attack
Varicella Zoster -- Sx, Dx, Tx
Diagnosis & I.D.
 Differential exclusion of: bacterial or enterovirus infections, contact dermatitis, disseminated HSV
 VZV DNA PCR, detection of VZV antigens in lesions by immunofluorescence
 Serology to determine immune status
o Prevention and Treatment
 Live attenuated virus (only herpesvirus vaccine that is clinically licensed)
 Live, attenuated virus-Oka strain : 2 doses given to young children. 15-20% of vaccinated individuals get infected with wild-type VZV that establishes latency & can reactive later in life despite immunization. vaccination significantly reduces severity of primary infection. Oka vaccine strain establishes a LIFE-LONG ltatent infxn, reactivation can occur but results in mild symptoms. Oka vaccine strain can be transmitted to immunocompromised. Immunization can limit Zoster -- Immunity in aged not as long-lasting, recommended in pop > 60yrs regardless of zoster occurence.
CMV -- structure, transmission
Structure
 dsDNA virus, encodes own DNA replication factors
 enveloped virus containing nucleocapsid
o Replication
 Unlike HSV Does not shut off host cell synthesis of DNA, RNA, or protein. / No thymidine kinase --> acyclovir does not work; Cell associated, poorly released from infected cell. Lytic infection – diverse
cell types; Latent infection – monocytes & CD34+ hematopoietic progenitor cells (bone marrow stem cells), Latent infxn with periods of lytic replication (lifetime infxn).
CMV lytic replication (slow 4 day replication cycle) --  Binding and penetration to cell (30 minutes)
 Entry/uncoating (1 hour)  nucleus to undergo transcription
 DNA replication (24-48 hours)
 Encapsidation (2-3 days)  envelopment/release (3-4 days)
CMV -- epidemiology, transmission
Epidemiology – humans are only reservoir
 Rate of seropositivity – associated with socioeconomic condition (40-80% in U.S., > 90% in developing countries)
 ~1:150 fetuses are infected during pregnancy
 10% symptomatic at birth = 1:750 newborns
 90% asymptomatic at birth  15% develop complications (8,000 children/year U.S.)
o Transmission
 Direct contact with virus-containing secretions
 Shedding without symptoms (saliva, breast milk, semen, cervical secretions, tears, urine)
 Blood transfusions, organ transplants
 4-6 week incubation period
CMV -- pathogenesis, Immunity
Pathogenesis
 Lytic infection in organ spreads to monocyte
 Circulate to blood stream
 (CD34+/CD38- myeloid precursor cells -->) Latent in mononuclear leukocytes & stromal cells of bone marrow. Only detect viral DNA but not infectious virus present
 Reactivation – latent myeloid progenitor differentiates into macrophage. 1 in 10,000 frequency of reactivation.  systemic spread. Suppression of immunity results in reactivation
o Immunity
 Innate – macrophage functions, IFN and NK cell activity correlate with resistance but cannot clear virus
 Cell-mediated – CTLs kill CMV-infected cells – up to 10% of all CD8 T cell (long-term) may be directed against CMV
 Humoral – may limit re-infection or reactivation Abs persist for life, directed against surface glycoproteins of viral (neutralizing). Lytic viral antigens gB, gH, pp65
 CMV immune modulation – MHC down-regulation, cytokine regulation, block NK cell recognition
CMV -- sx
Symptoms
 in healthy adults typically asymptomatic, If clinical symptoms -- mild mononucleosis or cold like fever. Usually mild dz and often unapparent. Myalgia, fever (2-3 weeks), liver function abnormalities (subclinical hepatitis), lymphocytosis (incr in number of lymphocytes and atypical lymphocytes), lymphadenopathy, Mononucleosis (heterophile AB-negative. 8% of all infectious mononucleosis due to CMV).
 Disease in immunosuppressed patients – i) transplant patients (solid organ and hematopoetic stem cell) - pneumonitis, esophagitis, gastritis, enterocolitis, hepatitis, retinitis, graft failure; ii) AIDS patients - retinitis, esophagitis, gastritis, enterocolitis, hepatitis, pneumonitis, peripheral neuropathy, encephalitis. [Responsible for as many as 50% of post-transplant deaths]
 Mononucleosis, pneumonia, G.I. infections, retinitis
 Most common viral cause of congenital birth defects. Virus can infect and cross placenta.1 in 150 babies infected. <20% of pregnant women have CMV in cervix at term. >50% of normal children 0-4 years old shed CMV in urine, oropharyngeal secretions. Primary infection 1st or 2nd trimester (mother is seronegative). 60% women have CMV before pregnancy --> 1% positive baby. 40% not have CMV -- 2% get CMV -- 30% positive baby.
o Very serious! – 33% chance that virus crosses placenta – fetal infection Second/reactivation infection (mother is seropositive)
o Immune protection, transmission occurs but fetal infection is less likely
 CMV disease in newborn – 1. Temporary -- “blueberry muffin babies” Petechial lesions (54%), small size at birth (47%), hepatosplenomegaly (40%), jaundice (38%), hemolytic anemia (11%), pneumonia (8%); 2. Permanent symptoms – unilateral/bilateral hearing loss (25%), vision loss (11%), mental retardation, intracranial calcifications (37%), microcephaly (36%), mortality (10-30%), seizures (9%)
CMV -- Dx and Tx
Diagnosis & I.D.
 Immunofluorescence, culture virus (on diploid fibroblasts -- Shell vial assay using immunofluorescence), RT-PCR
 Reed-Sternberg Cells. Owl's eyes in urine or other tissues (giant cells)
 Serology targets viral antigen gB IgG (prior exposure/infxn) and IgM (primary infxn, reinfxn, recurrence) antibodies against pp65 (note: mother can transfer these transplacentally)
 Viral culture performed during 1st week of life if baby is SYMPTOMATIC. -- Current CDC says to NOT test for CMV of mom or kid / check newborn if i) mother has seroconverted to IgG during pregnancy (require previous test); ii) mother has presence of both IgG and IgM during pregnancy.
 No test to rule out primary CMV infection (check for seroconversion during pregnancy)
o Prevention and Treatment
 If symptoms of CMV infection at birth  test vision and hearing regularly First 10 years, hearing/vision loss can develop
 Ganciclovir or foscarnet – for serious, life-threatening, or sight-threatening CMV. No Tx approved during pregnancy or in newborn
 Ganciclovir – synthetic nucleoside analog, activated by phosphorylation by viral kinase. inhibits viral DNA polymerase
 Foscarnet – structural mimic that inhibits pyrophosphate binding site on viral polymerase Inhibits DNA replication – more toxic / Cidofovir -- synthetic nucleoside analog, does NOT require phosphorylation, inhibits viral DNA polymerase.
 Acyclovir is ineffective – no thymidine kinase to phosphorylate acyclovir / Anti-CMV IgG (cytogam) given in parallel
HHV 6 - sx, dx, tx
o Roseola infantum
 High fever 4 days, irritability, malaise, lymphadenopathy, then rash in 10%, no sequelae
 Most common cause of admittance to ER with febrile seizures in infants (<2 years age)
o Symptoms
 4-7 day incubation
 Abrupt high fever 103-105oF for 4 days
 Rash, no fever  recovery without complications
o Replicates in CD4+ T cells, site of latency is unknown (likely salivary gland epithelium and lymphocytes)
o HHV-6 encephalitis – reactivation in immunosuppressed (seen in some stem cell transplant recipients)
o Detection – PCR and culture
o Treatment – Ganciclovir, foscarnet, cidofovir
Glanciclovir? Foscarnet? Acyclovir? Cidofovir?
Antivirals. Glanciclovir -- serious, life-threatening CMV. inhibits viral DNA polymerase. needs to be phosphorylated. Nucleoside analog; Foscarnet -- mimic structure inhibiting pyrophosphate binding site on viral polymerase. inhibits DNA replication. Toxic; Cidofovir -- nucleoside analog. does NOT require phosphorylation, inhibits viral DNA polymerase. Acyclovir -- thymidine kinase related.
EBV -- replication , path
Replication / Pathogenesis
 Epithelial cells of pharynx and/or salivary gland epithelium -- B lymphocyte infection
 Primary infection = mononucleosis. Proliferation of polyclonal B cells -- heterophile antibodies produced
o 5-20% of B cells infected in 1st week, then <1% Proliferation of Atypical T cell - Downey cells -- kill proliferating B cells Cytotoxic T cells result in lymphadenopathy. Latency III – infectious mononucleosis, PTLD
o Viral proteins made during proliferative but non-productive infection (immortalizing) – EBNAs, LMP1,2a,2b; EBERs (EBV-encoded RNA) -- infectious mononucleosis, Post-transplant lymphoproliferative disorder.
 Latency I/IIa - Memory B cell EBV association with cancers. EBNA1, LMP1, LMP2, RNA EBER1&2 -- Burkitt's, Hodgkin lymphomas, nasopharyngeal carcinoma.
 Reactivation in activated Memory B cells -- lytic, asymptomatic -- salivery secretions spread to others (“kissing disease”). (transmission by blood and saliva. Infxn of epithelium of pharynx and B cells) Lytic outcome – antigenic proteins characteristic of productive infection EBNAs (EB nuclei Ag), VCA (Viral Capsid Ag), EA (early Ag). Multiple stages of latency in B cells (latency reservoir)
EBV - structure
dsDNA. encode its own DNA replication factosrs.
EBV -- epidemiology, transmission, sx, dx, tx
Epidemiology
 Humans only natural host
 Infectious mononucleosis – usually at age 15-25 years, 1st exposure to EBV
o Transmission
 Contaminated secretions
 Persists in infected individuals for life
o Immunity
 Humoral – neutralizing Ab – no effect on virus shed. AB diagnostic
 Cell-mediated – CD8+ T cells & NK cells are effective and essential in lysis of EBV-infected cells
 Loss of T cell function results in B cell proliferative disease/lymphomas / Mononucleosis is proliferation of atypical T cells (Downey cells)
o Symptoms
 Commonly causes asymptomatic infections
 Infectious mononucleosis – (Latency III) Fever, lymphadenopathy, pharyngitis, malaise. Virus shed in saliva. 5-20% of B cells infected with EBV in first week. Polyclonal B cells produce AB by agglutination of animal RBC (Paul-Bunnell test - sheep rbc, Monospot test - horse rbc). Self limiting -- tx the sx.
 Post Transplant Lymphoproliferative Disorder (PTLD) – (Latency III) 1-33% of transplant patients depending on organ Stem cell transplant, especially if graft is T-cell depleted 40-70% mortality. EBV induced B cell proliferation. Arises in donor B cells or reactivation in recipient. Low risk if graft contains donor T cells.
 Burkitt’s lymphoma – (Latency I/IIa) B cell lymphoma of jaw and face found in children (5-10 years) in Africa Associated with Chr. 8 & 14 translocation: Ig promoter-myc proto-oncogene
 Hodgkin Lymphoma – (Latency I/IIa)
 Nasopharyngeal Cancer – (Latency I/IIa) EBV DNA in epithelial tumor cells
 AIDS associations Polyclonal lymphomas, Lymphocyte interstitial pneumonia (mostly children), Hairy oral leukoplakia of tongue
o Diagnosis & I.D.
 Infectious mononucleosis Agglutination blood test – detect heterophile antibodies Paul-Bunnell test (sheep RBCs); Monospot test (horse RBCs)
 PTLD – FISH (fluorescent in situ hybridization) for EBV early RNA (EBER) and PCR
o Prevention/Tx -- NO antiviral drugs or vaccines available against EBV. Reduce immunosuppression. Make EBV-specific T cell lines form donor and infuse them.
Retrovirus - classification, structure
Classification (based on genome)
o Simple
 Alpharetrovirus
 Betaretrovirus
 Gammaretrovirus
o Complex
 Deltaretrovirus
 Epsilonretrovirus
 Lentivirus – Human immunodeficiency virus (HIV-
1,2)
 Spumavirus / Structure and Composition
o Enveloped virus
o Capsid made up of structural protein (group specific antigens, product of the gag gene)
 Matrix (MA), Capsid (CA, or p24), Nucleocapsid (NC), Protease (PR)
 Capsid (CA, p24) -- icosahedral (HIV bullet shape)
 P24 -- diagnostic use to test for HIV infection
o Retrovirus genomic organization
 2 copies (diploid) of a positive ssRNA genome
 All have 3 genes (5’ end cap – gag, pol, env – poly A 3’ end) at minimum and in the same order gag -- encodes for MA, CA, NC, PR; pol -- encodes for RT (reverse transcriptase), IN (integrase); env -- encodes for SU (surface), TM (transmembrane)
Retrovirus -- Replication Cycle
Replication Cycle
A. Adsorption
a. Binds via ENV protein & host cell receptor -- HIV receptor is CD4/CCR5
B. Penetration and uncoating
a. Viral envelope fuses with cell membrane either at cell surface or in endosomes after endocytosis -- Antivirals – entry and fusion inhibitors
b. Genomic RNA only partially uncoated (goal is not immediate translation)
C. Reverse Transcription
a. Reverse Transcriptase
i. RNA-dependent DNA polymerase
ii. DNA-dependent DNA polymerase
iii. Error prone (~5 errors/100,000) -- rapid evolution, drug resistance
iv. Antivirals and inhibitors – AZT (Reverse Transcriptase is very important as a target for antiviral drugs, numerous inhibitors available for HIV therapy)
b. Integrated DNA (the “provirus”) is longer than the template RNA and has U3 and U5 duplicated at the ends to form the Long Terminal Repeat – provirus DNA circularizes
D. Transit to the nucleus
a. Integration requires viral dsDNA access to host DNA – many retroviruses cannot cross nuclear membrane and need cell division to integrate
b. HIV can cross nuclear envelope
E. Integration into host DNA
a. Integrase recognition/specificity for U3 and U5 ends; NOT specific for host DNA
b. ‘random’ insertion (there are "hot spots"). once integration occurs, virus is PERMANENT resident of the host cell's DNA. IN protein ALONE perfors the insertion.
c. Raltegravir – blocks integration
F. Viral RNA synthesis, host pol II (Proviral transcription) -- major role of the LTR is to direct synthesis of viral RNA
a. U3 contains binding sites for cellular transcription factors required for high level RNA synthesis
b. Only 5’ LTR is transcriptionally active (despite U3 is repeated on both ends)
c. Organization of LTR -- U3 contains binding sites for CELLULAR transcription factors required for high level RNA synthesis. Spectrum of proteins that bind influences which tissue/cells retrovirus is active in (tropism)
G. RNA processing
a. All RNAs are polyadenylated
b. Three fates of viral RNA
i. Full length RNA -- genomic RNA
ii. Full length RNA -- gag-pol mRNA
iii. RNA splicing -- env mRNA (splicing incomplete to preserve genomic or gag-pol RNA). most (50-80%) is unspliced.
H. virion protein synthesis (translation)
a. free ribosomes in cytoplasm
i. gag and gag-pol made as polyproteins from full length RNA (most abundant protein)
ii. cleavage by Protease required outside of cell
b. ER-bound ribosomes
i. Env protein made from spliced mRNA on ER bound ribosomes -- trafficked through ER-golgi, inserted into plasma membrane
ii. Cellular protease-dependent cleavage of SU (gp120):TM (gp41) protein in golgi (NOT good antiviral target because will probably have some host fn too)
I. assembly and budding
a. packaging – requires Psi – signal in only unspliced RNA (splicing removes Psi signal)
b. Budding – viral gag and gag-pol polyproteins recruit RNA and assemble under the cell surface -- gag interacts with env
J. capsid maturation (proteolysis)
a. proteolysis of gag and gag-pol by PR occurs after budding --> protein rearrangements and core becomes more dense.
b. Viruses are NOT infectious until proteolysis
c. HIV PR (protease) inhibitors: based on if proteolysis inhibits, viral particles still form but viruses are NOT infectious.
Retroviral mediated oncogenesis
Retroviruses discovered as agents from naturally occuring tumors in animals. / Non-transforming retroviruses
o Tumors take 6 mo-1 year to appear
o Do NOT transform cells in culture
o Viruses DO NOT contain oncogenes
o Tumors are caused by activation or inactivation of host genes
o Promoter insertion – viral promoter used (unregulated protein or wrong time)
o Enhancer insertion – cell promoter inappropriately turned on by U3 (activates cell promoter) – correct protein made at wrong time / Transforming retroviruses (“acute”)
o Cause tumors within weeks
o Transform cells in culture
o Viruses harbor a mutated copy of a cellular gene involved in growth control
o Most oncogene-containing viruses are defective (oncogene replaces 1 or more viral genes)
HIV -- structure, Vif, Vpu, Tat, Rev, Nef
Structure
 Bullet shaped core
 Genome organization – very extensive alternative splicing, numerous additional mRNAs and protein reading frames Gag, pol and env proteins + additional proteins: Vif, Vpr, Vpu, Nef, Tat, Rev / Restriction Factors – viral proteins that inactivate cellular restriction factors
o Vif (virion infectivity factor) – degrades cellular antiviral protein deoxycytidine deaminase - normally incorporates into virions, in next infection causes C-T mutations to trash viral genome
o Vpu (viral protein U) – inhibits protein tetherin which otherwise blocks release of virus from cells Regulatory proteins
o Tat (trans-activator of transcription) – absolutely required for transcription
o Rev (regulator of virion expression) – promotes transport of unspliced RNA from nucleus to cytoplasm - allows structural gene expression / Nef – decreases expression of MHC-I on cell surface of infected cells
HIV -- replication
Adsorption & entry Major receptor - CD4 (CD4 T-helper cells; limited in dendritic cells, macrophages) Co-receptors (tropism)
o M-tropic (R5 tropic) – infect primary T-cells and macrophages
 Initial infection and transmission, predominate in asymptomatic
 CCR5 – receptor for chemokines RANTES, MIP- 1α, MIP-1β (these chemokines can specifically inhibit M-tropic HIV)
 Selzentry (maraviroc) – CCR5 antagonist / Non-fuctional CCR5 caused by 32bp-deletion in CCR5 --> highly resistant to infxn.
o T-tropic (X4 tropic) – primary T-cells and T-cell line, not macrophages
 Disease progression, arise at AIDS stage of infection
 CXCR4 – ligand is SDF-1 (cytokine stromal derived factor 1) – can specifically block T-tropic HIV infection
 Fusion process Env contacts CD4 -- conformation change to expose co-receptor binding site Fusion domain (hydrophobic) enters cell membrane, engages CCR5 -- Snapback of N- and C- terminal regions of gp41 – brings membrane together and fuses T-20 (Fuzeon) – blocks ‘snapback’ -- expensive and resistance
Selzentry (maraviroc)?
CCR5 coreceptor antagonist (HIV M-tropic receptors).
SDF-1?
Cytokine stromal derived factor 1 -- ligand of CXCR4 (HIV T-tropic coreceptor)
RANTES, MIP-1alpha, MIP-1beta?
Chemokines that specifically inhibit M-tropic HIV (bind to CCR5)
T-20?
Fuzeon -- antiviral for HIV. blocks fusion "snapback" step.
HIV -- epidemiology, transmission
Epidemiology
 Estimated 1.4 million in North America living with HIV (33.4 million worldwide)
 Genetic subtypes – geographical distribution of different subtypes (“clades”) – U.S. -- group B. Main clades is Group M. Vaccine effective for one clade will NOT be effective for another clade.
 HIV jumped from non-human primates to humans (HIV-1 is more similar to SIVcpz than to HIV-2).
o Transmission
 Inoculation in blood
 Sexual transmission
 Perinatal transmission
 Not involved in transmission – close personal contacts (enveloped virus does not survive well outside body fluid)
HIV -- pathogenesis
Pathogenesis
 Initial HIV infection -- uses dendritic/macrophage Ag-presentation to infect CD4+ population
 Spread in lymph nodes (APC migration there) -- viral replication, immune responses. Major and constant site of replication even in asymptomatic individuals w/low viremia. Follicular Dendritic cells trap lots of virus in it -- but presents to T-cells that pass through. Marked deterioration in node FDC occurs as dz progresses. Loss of FDC -- increased viremia late in infxn. CD4 T-cells infected in the nodes > periphery in earlier phases of infxn. Predominant site of CD4+ T-cell depletion is the G.I. tract
 Decline in CD4 T-cells, subsequent immune dysfunction / Initial targets to encounter HIV in submucosa -- dendritic cells, macrophages, CD4+ T cells
1. Direct killing of CD4 T-cells by HIV replication -- i) membrane leakage & death. ii) cell fusion syncytia observed in culture and in some tissues, could kill uninfected cells by bystander effect.; 2. Indirect effects on infected CD4 cells
o Immune response – humoral (Ab + C’) and cell-mediated (CTL and ADCC). Important for clearing viremia.Soluble gp120 may bind uninfected cells, now susceptible to ADCC.
o Apoptosis – primed by cross-linking of CD4 by gp120 in infected cell (may also be induced by Tat or Vpr)/ absorbed RT in infected naive CD4 cells --> rapid apoptosis.
o Antigen diversity threshold – constantly changing HIV exhausts immune system
3. Impairment of immune system function -- Loss of CD4 T-cell function (severely compromised immune system). Infected macrophages dysfunctional --> aberrant immune fn.
HIV -- sx, Dx
Symptoms
 Acute infection & seroconversion, decreased CD4 T-cells – 2-8 weeks. Early, vigorous CTL, FDC, humoral response -- clears viremia (but high levels of virus production persists in lymph nodes). May experience flu- or mono-like symptoms
 Asymptomatic phase – gradual decline in CD4 counts. CD4 counts; CD4:CD8 ratio; viral load by PCR ARC - patients with low 'set point' have better prognosis. (AIDS-related complex) – may persist for years before progression to AIDS -- fevers, night sweats, weight loss, diarrhea, skin, inflammation, generalized lymphadenopathy
 Symptomatic/AIDS phase – CD4 cells depleted (<200/ul), viremia, immune system fails. Opportunistic infections -- Protozoan (Cryptosporidium, Toxoplasma), Fungal (Pneumocystis carinii, Candidia), Bacterial (mycobacterium, salmonella), Viral (CMV, HSV, hepatitis), neoplasms (Kaposi’s Sarcoma, non-Hodgkin’s lymphoma). HIV wasting syndrome. CNS degeneration – AIDS dementia (subacute encephalitis, memory loss, aseptic meningitis, neuropsychiatric disturbances).
o Diagnosis & I.D.
 Primary screen – Ab ELISA – detects Ab to virus, Rapid oral test (inexpensive, fast results); Ag ELISA -- detect p24 antigen earlier than Ab.
 Confirmation tests – 2nd ELISA Western (immune) Blot – serum from patients. uses patient Ab to detect HIV protein.
 RNA RT-PCR -- detect virus in blood / Real-time RT-PCR – quantitate virus in blood. very sensitive (<50 HIV RNa copies per ml), detects virus before seroconversion (high risk groups, new borns), can gauge viral load in asymptomatic patients with low titers (important for prognosis)
HIV - tx
Prevention and Treatment / since progression is related to viral load, may not have to completely block replication to remain healthy.
 Entry Inhibitors: Selzentry (maraviroc) – CCR5 antagonist
 Fusion Inhibitors: T-20 (Fuzeon) – blocks ‘snapback’ -- expensive and resistance, must be injected
 RT inhibitor: Nucleoside/Nonnucloeside analogs (AZT, etc.) -- resistance appears rapidly
 Integrase Inhibitor: Raltegravir
 Protease Inhibitors: extremely effective -- still a problem with resistance
 HAART – Highly Active Anti-Retroviral Therapy Cocktails or triple therapy -- virtually eliminate virus production in some individuals for many years (virus undetectable in plasma, increased CD4 cell counts, clinical benefit; setbacks -- not all ptn respond, regimen difficult to follow, toxic effects in long-term use. inaccessible pool of virus; Free virus & infected T cells -- cleared in ~2 months. (other compartments with longer life) Macrophages & FDCs -- cleared in 1-2 years. (3rd compartment) Infected memory T-cells -- would need >75 years to clear this compartment (therapy along does NOT suppress new replication enough to allow immune system to eradicate HIV form individuals). / Vaccine NOT WORKING
Virus-causing cancer: Indirect vs. direct. immunosuppressed individuals
Indirect
 Chronic infection causes cirrhosis, inflammation, tissue damage, high levels of cell division
 Increases probability that dividing cells develop mutations & chromosomal aberrations
 e.g. Hepatitis B and Hepatitis C
o Directly
 Some DNA viruses stimulate the cells to enter S phase of the cell cycle and ready themselves for DNA synthesis
 If virus does not complete its life cycle and kill the cell -- same viral proteins continue to direct the cell to override normal controls on growth
 e.g. papillomavirus
o cancers more common in immunosuppressed individuals
 Merkel cell polyoma virus (MCPyV) – (same family as papilloma virus) Merkel Cell Carcinoma – aggressive skin cancer in elderly & immunosuppressed Common deletion that renders virus unable to complete replication cycle
Viruses - association with human cancer: Hep B, Hep C, EBV, HHV8, HTLV1, HPV
Hep B & Hep C -- Hepatocellular carcinoma; EBV -- lymphoma, nasopharyngeal CA; HHV8 -- Kaposi's sarcoma (KSHV); HTLV1 -- adult T vell leukemia (lentivirus); HPV -- cervical cancer, head and neck cancer
Papilloma virus -- structure
Structure
 Member of papovavirus family; many sub-types (~100)
 Small circular, dsDNA genome. Infect cutaneous and mucosal epithelia hands, feet, anogenital tract. 1/3 sub-types infect genital tract (these are sexually transmitted) -- others may only cause warts.
 Early genes E1 and E2 – mediate replication and transcription of viral DNA
o E1 = major replication; E2 = transcriptional repressor; E4 – disrupts cytokeratins to facilitate virus egress
 Late genes L1 and L2 – compose capsid (not regulatory component of cell growth)
 associated with oncogenesis: E5 – stimulates constitutive growth factor receptor signaling - immune-evasive properties too; E6 – recruits a ubiquitin ligase that targets p53 for degradation (cell cycle and apoptosis regulation); E6 also induces telomerase expression (enables cells to maintain their chromosomal telomeres and avoid senescence); E7 – binds to Rb (G1 -- S regulation; Cdk4/cyclin D normally build up to inactivate Rb by phosphorylation) Net effect -- aberrant proliferation, no apoptosis, immortalization -- transformation
Papilloma virus -- path & sx
Pathogenesis/Symptoms
 Inoculation of epithelium -- hand, foot, throat, or cervix -- Must penetrate down to basal layer to initiate infection. Increased size/replication of stratum spinosum layer with infection. Normally only stratum basale cells replicate
 Local multiplication --> wart --> 1. Resolution (latency). 2. Cell transformation
 Cervical Intraepithelial Neoplasia Productive high risk HPV infection Expression of early genes, premalignant changes Abnormal p53/pRB functions; centrosome abnormalities
 Squamous Cell Carcinoma Viral integration, loss of E2 (transcriptional repressor) expression Dysregulated E6/E7  p53/pRB non-functional Increased genomic instability, additional cellular mutations / LSIL (low grade squamous intraepithelial lesion) -- CIN1. Productive infxn. very mild dysplasia. virus prduction, HPV infxn (most women stop here); HSIL -- (cellular gene deregulation) CIN - No virus production; CIN 3 - high E6 & E7, viral DNA integration starts; Cervical canver -- DNA integration, break in basal membrane. / HPV infxn can have many outcomes and many factors may influence this outcome. Earlier stages of acute & persistent infxn -- viral DNA is maintained as an episome; Devo of Carcinoma -- INTEGRATION OF DNA into host chromsome. E6 and E7 ALWAYS retained in cancer cells. Integration disrupts the expression of E2 genes (which is a transcriptional repressor) --> allows increased levels of E6 and E7 expression. Replication of integrated DNA triggers DNA amplifications adn chromosomal abnormalities. / Minimal HPV segment retained in cervical cancers -- L1-LCR-E6-E7-E1. / HPV -- also associated with formation of penile cancers, vulvar cancers, anal cancers and -25% of oropharyngeal cancers.
Papilloma virus -- Dx. Tx
Diagnosis & I.D.
 Pap smear – CIN I, CIN II, and cervical carcinoma (CIN = cervical intraepithelial neoplasia). Cytoogical evidence of displasia or neoplasia. detection of koilocytotic cells (vacuolated cytoplasm) which are rounded and appear in clumps. disadvantage -- already progressed a lot. read by people.
 Hybrid Capture Assay for HPV: 1. Release nucleic acids (clinical specimens are combined with a base soln that released target DNA --> 2. Hybridize RNA probe with target DNA (Target DNA combines with specific RNa probes creating RNA:DNA hybrids) --> capture hybrids (multiple RNA:DNA hybrids are captured onto a solid phase coated with universal capture AB specific for RNa:DNa hybrids) --> 4. Label for detection (Captured RNA:DNA hybrids are detected with multiple AB conjugated to alkaline phosphatase. resulting signal can be amplified at least 3000-fold) --> 5. detect, read and interpret results (bound alkaline phosphatase is detected with a chemiluminescent dioxetane substrate. Upon cleavage by alkaline phosphatase, the substrate produces light that is measured on a luminometer in Relative light Units (RLUs))
o Prevention and Treatment
 Vaccine – need for mucosal infection. need to recognize multiple high risk strains. could not administer vaccine that included oncogenes.
 Capsid protein L1 self-assembles into VLPs (virus-like particles) that resemble virions and induce humoral immunity (assembly into VLP -- "penton shape" may have more effect than just giving monomer.) / Vaccines containing purified VLP's -- induces protective, humoral immunity. AB present at mucosal surface prevent incoming HPV from establishing infxn.
 Both contains VLPs, both administered in 3 doses: Gardasil – HPV types 6, 11, 16, 18 – approved for females ages 9-26. recombinant L1 produced in yeast. aluminum adjuvant (Th2); Cervarix – HPV types 16, 18. anti-HPV 18 longer duration, increased circovaginal secretion AB, increased memory B cells. recombinant L1 produced in insect cells. AS04 adjuvant (Th1, Th2)
What is the virus causing 25% of oropharyngeal cancer?
HPV
FActors contributing to emergence of new virus dz (6)
Factors contributing to emergence of new virus disease
o Increased population and population density
 Rapid population increase, concentrated in developing urban centers with poor sanitation and health systems
 International trade (e.g. production/distribution of blood products; exotic animal trade - monkeypox in WI)
 Changes in land use
o Increased travel
 HIV – originated in Africa, quickly spread
 SARS – in Asia in 2003, spread rapidly to 20 countries worldwide
o Changes in social behavior
 Promiscuous, unsafe sex
 Intravenous drug use -- transmission of blood-borne dz
 Increased antibiotic/antiviral use – selection of resistant organisms
 Increased use of day care – place of rapid organisms exchange among previously unexposed individuals with immature immune responses
o Changes in environment
 Climate change (weather disasters/exposure, increase range of virus vectors - ex. mosquito), population movement (exposure to new human, animal, and arthropod sources of viruses not previously present in pop), habitat destruction (increased encounters with animals/vectors)
o Changes in industry/technology
 New health care procedures provide opportunity for infections (transplant, immunosuppressive therapy)
 Changes in food handling (e.g., vCJD, BSE)
 New I.D. methods permit I.D. of previously unknown agents (PCR, ELISA - serological test)
o Changes in microorganisms (mutation)
 Mutation of surface molecules – new tissue/host tropism
 Mutation to antigenic difference -- prior immunity is no longer effective
 Mutation to increase pathogenicity
 Mutation to antiviral resistance (HIV)
 Change due to reassortment of segmented genomes (flu)
Hantaviruses
Structure
 segmented negative ssRNA genomes
 [Replicates in cytoplasm similar to other negative strand RNA viruses]
 [Steals “caps” to prime mRNA synthesis]
o Epidemiology
 Hantaan Virus – 100,000 cases/year in China
 Hantavirus-induced Pulmonary Syndrome – >500 cases/year in U.S., increasing
o Transmission
 Host is deer mouse
 Transmisstion by close contact, or aerosolized virus from droppings or urine
 Increased contact with mice due to high rainfall, plentiful food, increased mouse population (main factor is WEATHER CHANGE)
o Symptoms
 Hantaan Virus - Fever, headache, hemorrhage, acute renal failure; 5-10% mortality
 Hantavirus-induced Pulmonary Syndrome - Acute onset pulmonary edema, shock, death with days. It is ENDEMIC in US.
o Prevention and Treatment - no therapy; reduce contact with rodents
Arboviruses -- structure, replication, transmission, ex. 3 types of dz. cause of emergence of the viruses/dz
Structure – enveloped, positive ssRNA
o Replication – replicate similar to other positive ssRNA viruses
o Transmission - arthropod-borne viruses / West Nile virus, Dengue virus / Fever +/- maculopapular rash, encephalitis, hemorrhagic fever / increased range of vector (dengue) or introduction of virus reservoir (bird, human, mosquito) into new area (West nile virus)
West Nile virus
(mild fever or serious encephalitis) Exposure to 1 of Japanese Encephalitis Serocomplex gives a person immunity to all
 Virus reservoir in birds – arthropod (mosquitos) serve as vector
 Horse or human – usually dead end hosts, viremia low
 Cases decreased recently (birds gaining immunity?)
 Mild fever: fatigue, swollen lymph glands, headache, skin rash on trunk, eye pain
 Encephalitis, meningitis: fever, ataxia, myelitis, seizures, G.I. symptoms, mental status change
 Diagnosis – high index of clinical suspicion + laboratory tests. Consider WNV – adults > 50 years, unexplained encephalitis/meningitis in late summer/fall Bird population deaths can be used to track disease spread in communities/ecosystems / vaccine -- available for horses, for humans in development
What are the 3 general types of dz caused by Arthropod-borne (Arbo)virus
Fever +/- maculopapular rash, encephalitis, hemorrhagic fever.
Dengue virus
(fever or more serious hemorrhagic fever and dengue shock syndrome) 4 serotypes. Infection by 1 serotype does not confer resistance to others
 Mosquito transmission from human (urban) or monkey (jungle cycle)
 100 million infections worldwide/year
 Dengue Fever “Breakbone Fever” -- Fever, muscle/bone pain, joint pain, lymphadenopathy
 Hemorrhagic Fever & Dengue shock syndrome -- Individual with antibodies against one serotype is infected with another serotype. Non-neutralizing Ab thought to increase infection of Macrophages --> release of inflammatory cytokines & vasoactive mediators --> Causes rupture of vasculature, internal bleeding, plasma loss, shock -- Mortality 10-40%. DHF/DSS on rise due to import of serotypes in new areas; Diagnosis
o Positive tourniquet test - >20 petechiae/inch^2 indicates capillary fragility
o ELISA to detect Ab’s -- test ot determine which Dengue types the ptn has AB against. Tetra-valent vaccine being developed -- shows promise. would need antiviral against ALL 4 serotypes. / Viral antigen detection -- immunofluorescence / Prevention -- VECTOR CONTROL IS KEY / Dengue is spreading due to re-emergence of the vector mosquito.
Dx -- Adult > 50 years of age, unexplained encephalitis (or meningitis) in late summer/fall
consider West Nile Virus
Monkeypox
Relatively rare disease occurring mostly in Africa
o Reservoir – rodents, monkeys
o Transmission – African squirrel --> African rats --> pet prairie dogs --> pet owners
o Symptoms
 12 day incubation
 fever, headache, muscle aches, backache, swollen lymph nodes, fatigue (flu-like sx)
 1-3 days after fever starts -- rash develops – raised bumps filled with fluid, then crusts, scabs, falls off
 Illness lasts 2-4 weeks
o Prevention and Treatment – Smallpox vaccine (monkeypox shares antigenicity to smallpox) / reason for emergence -- Change in behavior (pet choice) & movement of virus (and reservoir) into new areas as a result of commerce
HIV -- cause of emergence
- Environment – transfer of HIV from Chimp to human
o Population/urbanization – often spurred by war
o Lifestyle changes – more sex partners
o Poverty – commercial sex trade
o Travel/lifestyle – male flight attendant had 100’s of partners in the 1980’s
o Sex trade in Asia -- exported exposures to other countries
o Technology – infected blood products
Recognition of patterns by PRRs -- Epitope mutation and viral interference
Viral interference: Epitope mutation (small genomes mutate much faster. Doesn’t work as well for large genomes)
o Viral interference: infection of privileged site: HPV infects the basal layer of the stratum then moves up as the cells are differentiated. Infectious virions are released at the dead cell layer where there is no blood or Langhans cells – immune system won’t see them.
Viral product --> synthesis and secretion of IFN-alpha/beta (process explanation)
Viral products (dsRNa, ssDNa, methylated DNA) --> sensed by PRRs (ex. PKR, RIG-I - influenza virus, TLR) --> cascade of signaling thtough adaptors, kinases --> Activates transcription factors (IRFs bind to the ISRE - IFN stimulated response element, in nucleus) --> Synthesis and secretion of IFN-alpha/beta (induction of the ANTIVIRAL STATE in NEARBY cells)
Type I IFN activation of PKR & 2'-5' Oligoadenylate Synthetase
PKR: upregulated when IFN α and β bind to host cell --> PKR binds to dsRNA --> becomes autophosphorylated (activated) -- it is a PRR --> PKR then phosphorylates eIF-2α (eIF-2α delivers met tRNA to initiate translation. but when phosphorylated translation is prevented.) --> Shut down of protein synthesis (Translation inhibition)
 OAS: upregulated when IFN α and β bind to host cell. OAS binds to and is activated by dsRNA --> activated OAS catalyzes synthesis of oligoadenylate from ATP, making polymers of adenlyate 2-9' nucleotides long. These adenylate polymers bind to and activate RNAase L (an endoribonuclease) --> RNAaseL degrades mRNA -->Shut down of protein
synthesis (mRNA degradation)
IFN signal blocking by viruses -- Extracellular vs. Intracellular blocking (Herpesvirus, Adenovirus, Poxvirus, Rabies)
Extracellular IFN signal blocking
 Poxvirus (large genome. Have enough room to make proteins to escape immunity): encodes proteins to prevent IFN binding: Viral IFN α and β receptors made by poxvirus – soaks up IFNs extracellularly.
o Intracellular IFN signaling blocking
 Herpes virus: viral protein that directs cellular phosphatase to remove phosphates from eIF-2α -- can proceed with protein synthesis
 Adenovirus: encodes its own RNA ("decoy") which binds PKR to inhibit its activation.
 Poxvirus: encodes dsRNA binding proteins -- sequester dsRNA and prevent PKR activation.
 Poxvirus: encodes eIF-2α “decoy” that binds PKR to prevent it from phosphorylating eIF-2α./ Poxvirus: encodes "decoy" IFN reeptors -- sequester IFN before it binds to cellular receptor.
 Rabies: encodes “P” protein that binds STAT and prevents its translocation to the nucleus (IFN intracellular signaling molecule).
Key elements of Anti-Viral State (caused by IFN Type I (alpha & beta)
Type I IFN -- induced by dsRNA (viral life cycle product). Secreted from infected cells --> binds to receptors on other cells --> transduces a signal through the JAK/STAT pathway, incudes a large number of anti-viral genes. / Anti-viral response: upregulation of MHC-I and immunoproteasome levels (increases presentation of viral antigens on cell surface). Stimulation of NK cells, which then produce IFN gamma (Type II) -- NK killing 20-100 X better when exposred to type I IFNs or IL-12. Activation of PKR (protein kinase that phosphorylates EIF-2alpha and inhibits global protein synthesis. Activation of RNAse L by 2'-5' oligoadenosine. RNAse L degrades viral mRNA (and cellular RNA) and shuts down protein synthesis.
Anti-Viral State -- characteristics?
increased MHC Class I expression, increased PKR expression, increased 2'-5' synthetase expression, increased 2'-5' oligo A (A-A), increased viral mRNA degradation --> decreased protein synthesis, increased surface class I MHC, increased NK cells. (DNA is linked 3'-5'. here we have 2'-5' pollymers of ATP --> these polymers activate RNAse L which degrades mRNA)
Viral inhibitors of the IFN - induced antiviral response -- Poxvirus?
decoy IFN receptors. dsRNA-binding proteins (prevent PKR activation), EIF-2 alpha decoy (bind to PKR)
Viral inhibitors of the IFN - induced antiviral response -- Adenovirus?
decoy RNA (binds to PKR)
Innate immunity -- Cytokines
Secretion of soluble mediators: IL-1, IL-18, TNFα, IFNy, chemokines: IL-1/IL-6/TNF-a induce immune response components: fever, synthesis of acute phase proteins (complement), neutrophil mobilization, protein and energy mobilization, TNFa stimulates dendritic cells to migrate to the lymph nodes.
o viral interference: inhibitors/decoy homologs of these cytokines are produced
 IL-1 and IL-18 are processed to mature form by caspase. Pox virus encodes caspase inhibitor that blocks this interaction.
 Poxvirus encodes receptor “decoy” that bind circulating cytokines and prevent them from reaching their target cells
IL-1
induce immune response components
IL-18 -- function?
increases IFN-gamma production by T,B,NK cells.
Caspase?
Process IL-1 and IL-18 to mature form.
TNFa
stimulates dendritic cells to migrade to LN
Poxvirus -- mechanism of blocking Cytokine related immune response?
1. encode a Caspase inhibitor --> blocks IL-1 and IL-18 maturation and release; 2. encode soluble, secreted receptor "decoys" that bind to circulating cytokines and prevent them from reaching receptors on target cells.
(virus) innate immunity -- complement cascade related
Complement: opsonization and phagocytosis, inflammation, and lysis via formation of the membrane attack complex (MAC). This process is regulated by “control” proteins (CD59, DAF, MCP) on the surface of host cells that
block the formation of MAC. Bacterial and some enveloped viruses lack these “control” proteins so the MAC can form and activate lysis.
o Virus interference: viruses can encode homologs of complement control proteins that prevent the assembly of the MAC on their surface, or can encapsidate the control proteins when they leave the cell and take these proteins right from the host cell surface (ex. poxviruses, CMV, KSHV, HIV)
CD59, DAF, MCP?
control proteins that blocks complement activation.
Virus -- how to they evade NK cell killing? ex?
NK cells – IFNy production, direct killing of cells:
o NK cells have inhibitory receptors that bind MHC 1 on host cells – thus if it is a self-cell expressing many MHC1, NK cell leaves it alone.
o NK cells also have activating receptors that bind NK cell receptor ligands on host cells or foreign cells.
o If there are more activating receptors than inhibitory receptors, the NK cell will the kill the cell in question. This is the case when viruses downregulate expression of MHC I molecules.
o Viral interference:
 Viruses remove MHC-1 from the surface of infected cells so CTL cells don’t see them – remove some HLA-A and HLA-B, but leave HLA-C on the surface (HIV, CMV)
 Viruses can encode “decoy” MHC-1 molecules which interact with NK cell inhibitory receptors (CMV)
 Viruses can remove the activating NK cell receptor ligands from the cell surface (CMV) / encode inhibitory NK cell receptor ligands (CMV)
VIral immunoevasins -- 1. affect surface expression of MHC I; 2. other molecules in immunological synapse
Viral inference: affect surface expression of MHC I (CTLs won’t see the foreign peptides)
 Block proteasome degradation of peptides (CMV, EBV, herpesvirus)
 Degrade TAP transporter (mouse herpes)
 Block the TAP transport (CMV, HSV)
 Degrade class I MHC molecules (CMV)
 Tether class I MHC molecules in the ER/Golgi (adenovirus, CMV)
 Divert class I MHC to lysosome to be degraded (HHV-6 and 7, HIV)
 Accelerate internalization of class I MHC at the surface (HHV-8)
 Downregulate transcription of components of the MHC (adenovirus) / Viral inference: downregulate adhesion molecules and costimulatory molecules required for activation of T cell.
 ICAM-1 – HHV-8
 Costimulatory molecules (CD80/86 – B7) – HIV (Nef) and HHV-8
Virus -- mechanisms to prevent apoptosis
Induced apoptosis: infected cells often undergo apoptosis
 From outside: Fas-L and TNF  caspases  apoptosis. Inhibitors of apoptosis:
o Soluble, secreted TNF receptors (poxvirus, herpesvirus)
o Proteins that block signaling through the caspase pathway
o Proteins that remove the Fas (CD95) from the cell surface (poxvirus)
o Inhibitors of caspase the block steps of caspase activation and target protein cleavage (poxvirus, adenovirus, herpesvirus)
 From inside: p53 induces apoptosis in cells with DNA damage, Bcl2 (stops apoptosis) Inhibitors of apoptosis:
o Homolog of Bcl-2 (adenovirus, herpesvirus)
o Inhibitors of p53
Bcl-2?
anti-apoptotic protein (homologs are made by Adenovirus, Herpesvirus)
Viral inhibition of Chemokine signaling
Normally: viral infxn --> release of chemokines that mobilize cells of the immune/inflammatory response -- receptors have 7 membrane spanning domains. CC and CXC are main classes of cytokines / Viruses encode i) decoy chemokines that bind to receptors but do not signal (poxvirus, KSHV, herpesvirurs) and serve as agonists of authentic chemokines; ii) soluble chemokine-binding proteins that sequester chemokines (poxvirus); iii) chemokine receptor homologs (for the benefit of viral tropism and virus spread) (ex. herpesvirus, poxvirus)