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331 Cards in this Set

  • Front
  • Back
Complex neurocapsid
D Replication
Smallpox, molluscum
Clinical Features
- 1o, varicella or chickenpox – systemic / disseminated viral disease
- reactivated, zoster or shingles - localized viral disease w/ neuronal spread to an affected dermatome
- spread from animals to humans (dead end host, we are not reservoirs)
- more than 50% of the viruses known to infect man are zoonotic
- spread by vertebrates by biting, contaminated excreta
- also spread by invertebrates, like mosquitoes, ticks, sandflies
Arthropod-Borne Encephalitis Viruses
- must replicate in mosquito gut then move to salivary glad prior to transmissions
- peak is mid to late summer
- no human to human spread - human viremias insufficient to let humans be the reservoir
- Alphavirus genus of the family Togaviridae and the Flaviviridae family
Clinical features
- respiratory exposure
- 10-14 day incubation
- then 'ratcheting' high fever, cough, coryza and conjunctivitis
- rash first on head and neck
- unique red lesions (Koplik's spots) with white centers, appear on buccal mucosa
upper respiratory tract infections
- common cold viruses (adenoviruses, non-SARS coronaviruses and rhinoviruses)
- replicate in epi surface of nasal mucosa
- primarily in columnar and ciliated epi cells
Incosahedral neurocapsid
D Replication
HSV-1, HSV-2, VZV, CMV, Roseola (HHV-6, 7)
Accute to Chronic
- mild febrile illness, disseminated vesicular rash of clear blisters w/ irregular red margin – resolved in a few wks
- macules -> papules -> vesicles -> pustules -> scabs
- headache and malaise -> pruritic rash -> fever
- Complications are 2o infections of lesions, post-infectious encephalomyelitis, pneumonia if immunocomp (in adults form fusion cell to cell spread, Reye’s syndrome
Emerging Zoonotic Viruses
- most established for years in small, isolated animal populations
- Viral changes - reassortment (influenza), recombination (WEE virus), point mutation (chicken influenza)
- travel (smallpox, syphilis, dengue), or behavior (STDs)
- Vector changes - mosquitoes change range (yellow fever), birds migrate (West Nile virus)
- Environment – irrigation (Rift Valley Fever), agriculture (Argentine HF), natural climate changes
- *Eastern Equine Encephalitis (EEE)*
- Western Equine Encephalitis (WEE)
- Venezuelan Equine Encephalitis (VEE)
- encephalomyelitis
- 1o measles or giant-cell pneumonia in immunodef
- 2o bacterial pneumonia
- keratoconjunctivitis in kids with nutritional deficiencies
- subacute sclerosing panencephalitis (SSPE) - rare, follows 7-10 years after 1o
lower respiratory tract infections
- paramyxoviruses (parainfluenza virus, respiratory syncytial virus, and human metapneumovirus
- myxoviruses (influenza)
- SARS - coronavirus
- primarily cuase bronchitis, acute laryngotracheobronchitis (croup), bronchiolitis and pneumonia
Incosahedral neurocapsid
No Envelope
D Replication
Accute to Chronic
- reactivation of latent VZV
- like chicken pox, but larger lesions on the dermatome innervated by infected sensory nerve
- may be very painful
- usually if immunosuppresed (so odds increase w/ age)
- complication is post-herpetic neuralgia - hypersensitive to touch and T
Zoonotic Viruses
virus enters the body and replicates locally -> transient viremia -> infection of RES -> secondary viremia -> prodromal symptoms of fever, chills, headache, muscle ache, malaise -> after incubation period (2-14 days), other organs can infect -> more serious disease may occur
- *St. Louis Encephalitis (SLE)*
- Japanese Encephalitis (JE)
- Tick-Borne Encephalitis (TBE)
- West Nile virus
- Dengue virus
atypical measles
- in persons who received killed measles vaccine during 1963-1967 then got infected
- atypical rash (no Koplik's), and serious pneumonitis
The Common Cold
- acute resp illness - mild and self-limited
- inflam of the MMs of the nasopharynx (catarrh)
- watery nasal discharge (which may contain sloughed columnar epithelial cells)
- no fever
- from rhinoviruses (100+ antigenic types) or coronaviruses (2)
Incosahedral neurocapsid
No Envelope
D Replication
Accute to Chronic
Properties of the Virus
- like herpes virus
- enveloped - so easily inactivated
- rapid replication and ease of transmission so hard to exploit
Zoonotic Viruses
Clinical Features
- Inapparent infection is most common
- Fever, chills, headache, back pain, muscle and joint pain, with or without a rash
appearing on the third or fourth day
- if rash, slow convalescence (1o dengue fever, Colorado tick fever) and possibly hemorrhagic fever w/ blotches and orifice bleeding
- may die from hypotensive shock (Dengue hemorrhagic fever/ Dengue shock syndrome, Ebola virus)
- kidney targeted in hemorrhagic fever with renal syndrome
- liver targeted in yellow fever
- if acute respiratory syndrome w/ edema (SARS and Hanta pulmonary syndrome)
- if encephalitis (EEE, WEE West Nile, SLE)
Structure and Replication
- Togaviridae family
- (+) sense ssRNA
- Icosahedral nucleocapsid w/ 1 capsid protein w/ envelope (M and E)
- Replication in cytoplasm with budding at PM
Virus properties
- pleomorphic morbillivirus
- one molecule of (-) ssRNA
- a viral-encoded RNA dependent RNA polymerase
- a helical nucleocapsid
- a lipoprotein envelope (know more about spikes)
- acute inflammatory of pharynx
- sore and scratchy throat
- edema and hyperemia of tonsils and pharyngeal MMs
- from rhinoviruses usually
Incosahedral neurocapsid
No Envelope
D Replication
Pathogenesis of Primary Varicella-Zoster Infection
- non-specific binding in the nasopharynx
- initial replication in resp epi -> LNs -> viremia to liver and spleen
- 2o viremia mediated by PBMCs - transports cutaneous epi and resp mucosal sites (to spread)
- w/ hematogenous and neural spread -> latent state in the sensory nerve ganglia
- asymptomatically shed throughout the host’s life
Zoonotic Viruses
- difficult initially - easier as specific organs are targeted
- take a complete history - travel, pets, hobbies or jobs that might expose the Pt to animals or insects
- Serology, PCR
- wild birds resivour - mosquito persistently infected
- along eastern seaboard
- only a few cases a year, only 2% is Ab + in epidemics
- Aedes albopictus, “Asian tiger mosquito”, is new - might let virus be a bigger problem, since it can feeds on birds and humans
- human-to-human in aerosol in lab
Viral Spikes
- one with hemagglutinating (H glycoprotein) activity
- one with cell-fusing (F glycoprotein) activity - F displayed on infected cell
- Morbilliviruses have no neuraminidase activity on spikes and induce BOTH nuclear and cytoplasmic inclusion bodies
- F is inactive precursor (Fo) cleaved by host in Golgi
- envelope must fuse to host (via F) for infection, spread and multinucleate formation
- inflam of larynx MMs
- w/ common cold and influenza
- lowering of the normal pitch, hoarseness, aphonia
- from influenza, sometimes rhinoviruses, adenoviruses and parainfluenza viruses
ssDNA (+/-)
Incosahedral neurocapsid
No Envelope
- croup
- acute, involving the larynx, trachea and bronchi
- kids under four
- high fever and blockage of the larynx and perhaps bronchi
- dyspnea and creaking notes
- typically due to one of the parainfluenza viruses
HGV etc
? if fulminant
Zoonotic Viruses
Epidemiology of Hemorrhagic Fever Viruses
- Vectors are rodents (Lassa fever, Hantavirus with renal syndrome, Argentine HF, Bolivian HF)
- Arthropods (Yellow fever, dengue, Rift Valley fever)
- Ebola and Marburg viruses have unknown vectors
- Human to human spread in Ebola, Marburg and Lassa fevers
Clinical Features
- Most subclinical
- febrile illness, may lead to encephalitis (50-75% fatal)
- 20-12 day febrile illness, then fever, stiff neck, loss of consciousness - may go to seizures, coma and death or it may resolve
Epidemiology and Transmission
- universal childhood infection
- spread by droplet - shed prior to symptoms
- both are non-seasonal and non-epidemic
- maternal protection for first six months
- immunity primarily cell-mediated
- 1o disease confers lifetime immunity to 1o, but shingles may develop due if immunocomp (age) – then protected from shingles
- inhalation to RT mucosa ⇒
regional LNs ⇒ primary viremia
- RE system ⇒ 2o viremia ⇒
lymphoid cells ⇒ lesions
- rash from CMI response
- infections probably involve CNS (usually asymptomatic) and
growth curve is arrested
Incosahedral neurocapsid
RT Replication
- inflam of tree
- ass. w/ generalized resp infection
- hyperemic and edematous MM ⇒ increased bronchial secretions
- cough to clear them
- destruction of epi
- accompanys a variety
Zoonotic Viruses
Treatment and Control of Hemorrhagic Fever Viruses
- supportive – restore physiology and nutrition
- Ribavirin for arenaviruses (Lassa fever, Argentine and Bolivian HF) and bunyaviruses (hemorrhagic fever with renal syndrome)
- Vaccines available for yellow fever and Rift Valley fever
- Dengue vaccine most needed and most problematic – must get all 4 strains or it will increase your likelihood
- moves from the blood ⇒ endothelial cells ⇒ nerve cells
- symptoms from viral action on nerve cells host imfla
- EEE is cytolytic - apoptosis of infected cells - IFNs important
- based on presentation and contact history
- fluorescent Ab of lesions
- culture provides the definitive diagnosis
HAV structure
- same as poliovirus (but does NOT inactivate host cell
protein that associates with capped mRNAs)
- Non-enveloped, icosahedral
- 60 capsomers ( w/ VP1, VP2, VP3, VP4)
- only one serotype
- natural infection produces lifelong permanent immunity
- neutralizing Ab directed at H
- can cross placenta (6 mos)
- agammaglobulinemics demonstrate a normal disease course
- cell-mediated immunodef ⇒ persistent infection
- concomitant depression of CMI to a wide variety of non-measles antigens
Incosahedral/Helical neurocapsid
RT Replication
- acute inflam and necrosis of the bronchiole epi
- before the age 2
- acute onset of wheezing and hyperaeration, tachypnea and resp distress
- from resp syncitial virus
Pulmonary Zoonotic Viruses
- Sin Nombre (Hantaan virus) gets mice in Americas w/ no apparent ill effects - shed in urine and stool, transmitted to humans via aerosol
- SARS coronavirus from palm civet cats (probably)
- both spread via human to human
Treatment and Diagnosis
- recovery due to development of Ab to envelope glycoproteins
- diagnosed by presentation or w/ serological tests like IgM ELISA
- No vaccine or treatment
Prevention and Treatment
- kids over 1 yr get one attenuated vaccine
- Acyclovir (or penciclovir) may terminate the viremia, reduce shedding, lessen severity
- Zoster immune globulin given to exposed non-immunes
HAV genome
- + sense, ssRNA that functions as mRNA
- translated as one ORF into polyprotein then processed by viral-coded proteases
- very contagious from aerosolized droplets (sneeze)
- survives in droplets for hours
- infected can spread 4 days before rash to 4 days after
- hight mortality from lack of adequate nutrition and health care, its immunosuppressive
- no animal reservoir
- rapidly “burns itself out” in isolated rural areas
Incosahedral neurocapsid
No Envelope
R Replication
HAV, Polio, Coxsackie, ECHO, Rhinovirus
- inflammation of the lungs
- 6th death cause
- destruction of ciliated epi
- diffuse congestion of alveoli w/ erythrocytes - fluid may be seen
- from RSV and parainfluenza viruses in children
- influenza viruses in adults
Pulmonary Zoonotic Viruses
Treatment and Control
- Rodent control, exposure control
- No drugs
Structure and Replication
- Flaviviridae family, like HCV - can cause yellow fever
- (+) sense ssRNA
- Icosahedral nucleocapsid w/ 1 capsid protein w/ envelope (M and E)
- Replication in cytoplasm with budding at internal membranes
Clinical Features
Presents differently among
- normal
- fetuses
- immunosuppressed
HAV translation
- NTRs at the 5’ and 3’ ends.
- 5’ end not capped
- ribosomes enter at IRES in 5’ then a Viral protein VPg covalently linked at 5’ and does RNA replication, and packaging, uncoating and penetration
Clinical symptoms
Incosahedral neurocapsid
No Envelope
R Replication
HEV, Norwalk
Structure and Replication
- naked icosahedral particles
- linear dsDNA
- several dozen serotypes, divided into subgroups (A-F)
based on antigenicity RBC agglutinatation ability
Encephalitis Zoonotic Viruses
- EEE, WEE, SLE, West Nile
- Mosquito vectors, so usually seasonal
- we are dead end host
- Migratory birds play an important role
- 1o unremarkable, usually in childhood
- most adults seropositive
- in (-) adults, 1o from children shedding in urine, saliva and feces
- adult 1o -> mild pharyngitis or EBV-like mono
- after 1o, symptoms cease; viral shedding falls but may recur
- Protective humoral immunity directed to envelope proteins
- CTLs do inflam response
HAV-infected hepatocyte
- translation of host mRNAs by usual cap-dependent process
- translation of viral mRNAs by CAP-independent process via IRES in 5’ NTR
- not cytolytic
- replication doesn't overstress the hepatocyte
- IRES not efficient at loading host ribosomes
- no therapy
- A two day course of vitamin A reduces severity in kids
- prevent w/ attenuated vaccine (MMR)
Icoashedreal Nucleocapsid
No Enveolpe
R replication
- genes E1A and E1B mediate transformation by deregulating cell cycle control by interacting w/ pRB gene
- not linked to human cancers
- can maintain a long-term ass. w/ host by persisting in lymphocytes for years
- discovered accidentally in cultured uninfected adenoidal tissue, from absence of immune surveillanc
Encephalitis Zoonotic Viruses
Treatment and Control
- Rodent control, exposure control
- Supportive care
- immune serum might help
- no drugs or vaccine
Congenital Infection
- if infected for the first time in pregnancy, may transmit to fetus
- in 1st trimester -> severe birth defects
- if later, congenital abnormalities
- (+) women w/ recurrent infection rarely transmit it
- Affected babies may appear normal, but have progressive damage to NS, esp hearing - very common
- Protective humoral immunity directed to envelope proteins
- CTLs do inflam response
HAV Diagnosis
- serology for anti-HAV specific IgM
- detection of an immune response at same time as onset of clinical symptoms implies immunopathogenesis
Measels Vaccine
- give first dose at a min of of 12 months
- give second dose at least 12 months later; usually 4-6 yrs
- window of susceptibility
- more than >90% covered
Icoashedreal Nucleocapsid
R replication
WEE, VEE, EEE, Rubella(sphere nucleocap)
clinical features
- can infect and replicate in RT, eye, GI, bladder, liver
- 5-10% of acute RI in kids
- also causes ARD, a syndrome from fatigue and crowding among young military recruits
St. Louis Encephalitis Virus
Clinical Features
- most prevalent arthropod encephalitis viruses in US
- most subclinical
- may begin w/ fever, malaise, headache -> encephalitis, meningitis, & febrile headache
- ESPbad for the elderly due to pre-existing conditions
- saliva of infected animal
- multiplies in striated muscle and CT (days -> months)
- reaches nerve endings _> passively spread in axoplasm to spinal ganglia and replicates -> faster pace to the spinal cord -> brain -> salivary glands via efferent nerves
- may develop severe disease after infection
- interstitial pneumonia, retinitis, enteritis and disseminated disease
- a high % of AIDS patients shed
- ½ have infection at somepoint
- primary post-transplant infection, esp bone marow
HAV pathogenesis
- likely a GI site for primary replication ⇒ liver by viremia
- hepatocytes probably damaged by cytotoxic T and leads to release of virus into blood,
- no chronic carrier state, lifelong immunity
- no progression to carcinoma
Clinical Features
- 18 day incubation
- viremic spread to parotid and presents as swollen salivary glands
- 1/3 infections subclinical
- can involve the epithelial cells of organs
Icoashedreal Nucleocapsid
R replication
HCV, SLE, Dengue, Yellow fever, West Nile
- worldwide
- sporadic to epidemic
- mostly fecal/oral in kids, but can occur via the resp route
St. Louis Encephalitis Virus
- mosquitoes winter reservoirs in winter, transmission begins in spring w/ birds as host
- human disease peaks from July - Sept - 50/year
- 5-15 year outbreak cycles
Clinical Features
- 2-8 wk incubation depending on amt of inoculum, virulence, proximity to neural tissue (head and neck wounds the worst)
- 2-4 day prodromal period
- 1st fever, headache, malaise, sensations at the wound site
- then increased irritability, anxiety, depression, sensitivity to sound and light
- difficulty swallowing
- generalized encephalitis develops and is always fatal
Properties of the Virus
- like herpes (HHV-5)
- largest herpesviruses genome
- it has a restricted host range
- it is sensitive to heat, low pH, lipid solvents (envelope)
HAV immune response
- humoral IgM - later supplanted by IgG
- CMI responds with cytotoxic lymphocytes
- clinical symptoms after viral shedding stops - serum ALT, AST rise
- all infected cells cleared from liver and replaced by new
- resolution ⇒ recovery ⇒ immunity
- in young, asymptomatic ⇒ response of less mature CMI??
- orchitis in 25% of males, worse and more common if post-puberty -> sterility
- aseptic meningitis in up to 50%, usually subclinical
Helical Nucleocapsid
R replication
SARS, non-sars
- vaccines to prevent disease by certain adenovirus types
- vaccination -> asymptomatic virus replication in GI
- not for civilians - concerns for spread of non-attenuated virus and oncogenic potential
St. Louis Encephalitis Virus
- consider if encephalitis, meningitis or febrile headache in July - September, esp old
- PCR of blood, CSF or tissue
- IgM in serum or CSF by ELISA
- Ab testing of paired sera
- immunofluorp for SLE Ag in cells of urine sediment or CSF
- in resource-poor nations, mainly from domesticated animals (dogs)
- in developed countries from wild animals (vaccination)
- 74% in US from bats
- rapidly increasing epidemic in SE US in raccoons and foxes
Pathogenesis and Immunity
- outcome determined by host immunity
- 1o in salivary gland epi -> asymptomatic viremia and shedding
HAV epi
- humans only reservoir
- hard to control since virus sheds in feces for two weeks before symptoms
- most mild or asymptomatic
- stable in the environment
- spread person to person via fecal-oral spread during sex, esp anal sex
- problem day care centers
- fecal contam of source, esp water w/ shellfish
- in food if poor hygene or uncooked fruits or gebbies
Viral Properties
- pleomorphic paramyxovirus
- transcription, replication and assembly in cytoplasm like the measles virus
- envelope has 2 spikes
- one with H and N activities, the other w/ F activity
Helical Nucleocapsid
R replication
Structure and replication
- (+) polarity ssRNA
- naked icosahedral capsid
- capsid from copies of 4 proteins, like picornavirus
- 30-40% of winter colds
- replication T sensitive at 37° - limits to URT
St. Louis Encephalitis Virus
- no vaccine, treatment limited to supportive therapy
- reduce of vector populations
- hard to do since expansion of mosquito habitat, insecticide resistance, new vectors species
- definitive diagnosis from post-mortem examination of the animal
- neck biopsy can be used in symptomatic humans
- darkly-staining viral nucleocapsids (Negri bodies) in cytoplasm of CNS cells
Epidemiology and Transmission
- ubiquitous, more in urbar areas
- humans only reservoir
- in all body fluids, close contact transmits
- (+) can shed for years
- sources are daycare kids, immunocomp shedding more, (+) moms milk
HAV treatment
- practice proper hygiene
- Vaccine, need 2-3 doses of killed - recommended for travelers - required for some school entry, given to children at ≥ age 2
- no drugs available
- used to give immune serum globulin to prevent effects, but now pooled gamma globulin is becoming low in anti-HAV
- replicates in URT, then to LNs ⇒ viremia
- replicates in the epi cells of various organs (parotid)
- cell lysis then multi nucleated giant cells (cell fusion)
Helical Nucleocapsid
R replication
Mumps, Measles, RSV, parainfluenza
- subclinical in most - misdiagnosed as EBV.
- likely the cause of mono if EBV negative
- found in WBCs by immunofluorescence.
- shell vial assay detects w/in within 24 hours.
- in immunocomp - serology for IgM and IgG
- in congenital - infant’s urine and saliva
- in immunosup - culture a biopsy
West Nile Virus
- severe meningoencephalitis in elderly in israel
- came to US in 1999, found in wild birds, horses and humans
- 2002 outbreak, most cases from mosquito bite, some from transplants
- blood is now screened
- usually in old
- if pregnant, rarely associated with spontaneous abortion and neonatal illness, but not birth defects - but intrauterine infection possible
Prevention and Treatment
- vaccination of domestic animals
- wound site immediately cleaned to and injected w/ human rabies hyperimmune globulin to neutralize slow growing virus
- attempt to develop active immunity in the exposed person with a vaccine
HEV structure
- + sense ssRNA; three ORFs - one translated as a polyprotein processed by a viral protease
- classified as a calicivirus (general similarity to HAV)
- (+) polarity ssRNA
- helical nucleocapsid w/ envelope containing 3 or 4 glycoproteins in spikes
- pleomorphic shape
- 20-30% of winter colds
Immune response
- only one serotype
- immunity lifelong
- neutralizing Abs directed at the HN envelope protein
- Ab in saliva signals the end of virus excretion
- can cross placenta
Helical Nucleocapsid
R replication
Prevention and Treatment
- no good treatment
- no viral TK, so no acyclovir or penciclovir
- ganciclovir works (still analog of dG, but a viral kinase will phosphorylate it)
Transmissible Spongiform Encephalopathies (TSEs)
Kuru, Creutzfeld-Jakob Disease, and Mad Cow Disease (BSE)
Clinical Features and Pathogenesis
- transmitted by inoculation or ingestion of diseased nervous tissue
- incubation can last decades
- death is usually months after symptoms appear
- loss of motor control, dementia, wasting, with progressive loss of brain function -> death
- large vacuoles in the cortex and cerebellum
The Picornaviridae family
- genus Enterovirus
- poliomyelitis virus
- echoviruses (enteric cytopathic human orphan virus)
- enteroviruses
- coxsackieviruses (Coxsackie, NY …site of first isolation)
- genus Rhinovirus (including “cold” viruses)
- genus Hepatovirus (hepatitis A virus)
Rhinovirus and Coronavirus
- confined to URT
- minimal and self-limiting
- may set stage for more serious bacterial infections (sinusitis, OM)
- only coronavirus can cause more serious disease in kids like bronchiolitis, bronchitis and pneumonia
HEV clinical features
- fecal-oral spread - similar to HAV
- much higher incidence of fulminant hepatitis, with
an especially high mortality (20%) in pregnant woman
- spread via aerosolized droplets, esp in winter and spring
- shed for 7-10 days, from 6 days prior to symptoms
Helical Nucleocapsid
R replication
Clinical Disease
- Smallpox
- Vacinnia
- Molluscum contagiosum
- Zoonotic poxviruses
Transmissible Spongiform Encephalopathies (TSEs)
Kuru, Creutzfeld-Jakob Disease, and Mad Cow Disease (BSE)
Properties of the Agent and Replication
- prion disease - small, proteinaceous infectious particle that resists inactivation by procedures that modify nucleic acid
- the altered protein (PrPsc) forces normal proteins (PrPc) in alpha helices into abnormal or beta sheets -> fibrils and amyloid plaque
- very hard to inactivate (remember the brains in lab)
- small, (+) ssRNA
- spherical, icosahedral, acid stable
- poly (A) tail and a 5’ VPg
- NTRs flank coding regions
Rhinovirus and Coronavirus
- strain specific immunity after infection
- lots of serotypes (over 100 r)
- c immunity limited - can be re-infected w/in 2 years
HEV Pathogenesis
- no chronic carrier state
- no progression to hepatocellular carcinoma
- clinical symptoms alone
- swollen parotid
- virus may be cultured
- antiviral Abs may be found in the convalescent serum
Helical Nucleocapsid
R replication
Lassa, LCM, the 2 HF's
Clinical Disease
- eradication in 1977
- presented as either variola major or minor
- rash is macules -> papules -> vesicles -> pustules -> crusts
- major form of had 10 - 30% mortality, partly due to disruption in food production
- Monkeypox in African is transmissible to human
Creutzfeldt-Jakob Disease
- rapidly fatal, presenile dementia of old people
- memory loss w/ confusion, vertigo, blurred vision -> dementia and motor dsfunction
- usually acquired sporadically, but some genetic from amyloid precursor protein mutation
- can be transmitted by surgical instruments, transplanted dura and corenea
- no immune response, no treatment , and no recovery or remission
- initially replicates in the human intestinal tract
- attaches to receptors (which determine tropism)
- viropexis (RME) does penetration and uncoating
- translation is cap-independent
- cap-binding complex (CBC) shuts of host proteins
- uses RNAdependentRNA polymerase
- asymmetric, many (+) molecules made few (-)
Rhinovirus and Coronavirus
- nose-hand-nose b/t people
- r can survive for hours on environmental surfaces
- reducing spread via handwashing, ventilation
- similar to HAV
- endemic in 3rd world from contamination of water
- uncommon in US, only from going abroad
- important to ask about pregnancies
- its been found in US pigs, be careful w/ hog farms near water
- immunization with live attenuated vaccine (MMR)
- no antiviral therapy
Helical Nucleocapsid
R replication
Marburg, Ebola
Clinical Features
- used as propylaxis of variola
- following subcutaneous inoculation is a papule
- lesion has same pattern as smallpox w/out spreading
Bovine Spongiform Encephalopathy (BSE)
- scrapie is a naturally occurring spongiform encephalopathy of sheep
- developed from feeding cattle scrapie-infected sheep by-products - Mad Cow Disease - may have adapted to be more stable in humans
Clinical Features
- most subclinical - malaise, fever, headache, nausea
- “abortive poliomyelitis”, as symptoms only last a few days
- rarely can cause aseptic meningitis (resolves in 2-10 days)
- rarely, paralytic polio - most significant paralysis presents w/in a few days, and most recovery is w/in 6 months - “progressive post-poliomyelitis muscle atrophy”
- 25-40% have additional deterioration decades later from effects of aging
Rhinovirus and Coronavirus
- Capsid-binding antiviral agents (WIN compounds) prevent
virus binding and entry for R
- Anti-receptor compounds
against ICAM-1 - prevent R binding and entry - prevents, doesn't treat - adding soluble ICAM-1 receptor helps - fast resistace
- hard to treat b/c no early clinical recognition, no rapid differentiation, short half-life
- no vaccine
HEV Diagnosis
- clinical signs combined with history and exclusion
- serology requires special tests (available through CDC)
Rubella Clinical Features
- normally like measles
- 14-21 day incubation
- most cases subclinical
- starts w/ rash (face ⇒ extremities) and lasts 3 days
- if acquired later in life (by males or non-pregnant females) its uncomplicated
- if pregnant, congenital rubella syndrome and high risk of spontaneous abortion
- congenital often results in hearing loss or cataracts - can take months to manifest - as kids, they can be carriers and shed
? Nucleocapsid
R replication
Clinical Features
Molluscum contagiosum
- self-limiting infection of the skin
- small umbilicated nodules - may last from months to years
- increased severity in AIDS iincreasing frequency in genital infections
Variant Creutzfeldt-Jakob Disease (vCJD)
- like CJD, but ataxia and memory loss more common
- younger age group (16-45 years), mainly in UK
- methionine homozygosity at position 129 of the prion protein predisposes to CJD, kuru, and vCJD
- possibly from exposure to BSE - similar glycosylation patterns, abundant, distinct amyloid plaques in both, and mice inoculated w/ either show similar disease
- alimentary tract via mouth - shed in feces for several weeks
- 1o replication in OP mucosa, tonsils, LNs - ingested to gut and adjacent lymphoid tissue
- 1o viremia infection of Peyer's patches and mesenteric LNs - spread to SC, meninges, and muscle
- paralysis after 10 days - direct destruction of the neurons or edema-induced damage of the neurons (reversible)
- fatal outcome if infection gets the CV centers of the medulla oblongata
Respiratory Syncytial Virus
- irregular shape
- (-) sense ssRNA
- helical nucleocapsid w/ envelope (3 spiky glycoproteins)
HEV Treatment
- supportive treatment only (no anti-viral therapy)
- recombinant vaccines are still under development
Rubella Virus Properties
- spherical nucleocapsid w/ envelope - Togaviridae family
- no RNA-dependent RNA polymerase in the virion
- one molecule of (+) RNA
- replication and maturation are confined to the cytoplasm
- infectious virions bud from the cytoplasmic membrane
HCV structure
- nucleocapsid protein
- E1 and E2 are glycoproteins present in the viral envelope
- NS include proteases, and an RNA dependent RNA polymerase
- substantial genetic heterogeneity - six genotypes (1, 2 and 3 are most prevalent in the US) and 100 subtypes
Icosahedral necleocapsid
No envelope
R replication
Clinical Features
Zoonotic poxviruses
- transmitted by direct contact
- occupational hazard
- self-limiting lesions on hands or face
- orf virus of sheep or goats, and cowpox
- poliomyelitis not endemic (unlike other enteros) b/c of vaccination
- bad in Sub-Saharan Africa and South Asia
- in US, only in immunocompromised vaccinees, imports, vaccinated contact
Respiratory Syncytial Virus
- G glycoprotein binding initiated infection
- penetrates via envelope fusion w/ PM (F mediates)
- events in cytoplasm
- transcribed by virion associated polymerase
- nucleocapsids bud through PM
- retrovirus – enveloped, RNA
- uses reverse transcriptase, RNase H, integrase, protease
- droplets ⇒ nose and local LN
⇒ viremia ⇒ organs and skin
- no fusion protein, so no cell to cell - viremia
- shed for 1 week after rash
- infection -> lifelong immun
- Abs cross the placenta
HCV genome
- + sense ssRNA
- no 5’ cap; IRES in 5’ NTR
- no virion-associated polymerase
- one ORF translated as one polyprotein then cleaved by cellular and viral proteases
high fidelity replication
DNA based
- large, complex, dsDNA
- replication in the cytoplasm
- have DNA-dependent RNA poly in nucleocapsids
Non-poliomyelitis enteroviruses
- usually no pandemic, just periodic sweeping every few years
- most mild or asymptomatic
- usually in kids in summer
- lower socioeconomic areas
- often found shellfish harvesting water
Respiratory Syncytial Virus
Clinical Features
- 4 to 5 day incubation
- 6-10 day recovery for kids
- <1% mortality unless immunocompromised
- bronchiolitis characterized by lymph infiltration & edema
- pneumonia characterized by rales or infiltrates
- no deepter than superficial layers of resp epi
Replication strategy
- Attach via CD4 protein receptor (chemokine as a co-receptor to fuse)
- RT and RNase H copy in DNA, then that’s transported to the nucleus where integrase inserts viral DNA into host chromosome
- large precursor proteins assemble then protease cleaves
- RT and protease are current drug targets
Rubella Epi
- springtime epidemics every few years - endemic worldwide
- unique togaviruses - it is neither infects nor is transmitted by arthropod
- outbreaks due to gaps in our vaccine coverage are a concern
HCV Clinical Features
- like acute HBV infection w/ lower serum ALT
- often sequential ‘episodes’
- many asymptomatic infections
- 40% of chronic carriers later develop cirrhosis which progresses into carcinoma
low fidelity replication
RNA based
RT based
Pathogenesis and Immunity
- inhalation ->replication in URT, LRT -> infection of M’s -> LNs for replication and cell-associated viremia (asymptomatic and non-infectious)
- replication in the spleen and bone marrow -> 2o viremia and replication in dermis -> skin for symptoms, OP form spread
- clinical signs nondescript - use knowledge of a current epidemic
- specific viruses identified via immuno-serological techniques
- appropriate specimens are stools, rectal and throat swabs
- mixed infections of enteroviruses common
Respiratory Syncytial Virus
- mediated by secretory Abs, serum Abs and cytotoxic T
- get maternal Abs
- multiple re-infections does immunity in older children
- secretory neutralizing IgA Abs better on nasal mucosa than serum, but not great
- cellular immunity ok, but short-lived
- local immunity most important in URT, serum Ab
best in LRT
Clinical Features and Pathogenesis
- progressive loss of CD4+ helper Ts -> immunodef
- Acute Infection - levels of virus present w/in 6 months - some immune insult that can’t be repaired by controlling viral replication later on
- Chronic infection - high rates of replication and immune clearance – sometimes and aggressive form uses a different co-receptor -> more rapid disease
- CD4+ T cell count drops below 200
Rubella Diagnosis
- usually clinical symptoms
- tests for immune status of women of childbearing age
- can be cultured in lab
HCV pathogenesis
- damage to hepatocytes is apparently from cytotoxic T's and virus-induced cell death
- biopsies show most cells w/ no CPE, no HCV Ag or RNA,
but bile duct damage, steatosis and lymphoid follicles
- IFN response key for viral clearance
- most become chronic, leading cause of chronic cirrhosis and requests for liver transplant
- causes PHC - 40+% die
very low fidelity replication
HIV and HCV - every "clone" is different
Rubella Treatment
- vaccination of children
- medical people are often required to be immune
- vaccine is very effective and long-lived
Epidemiology and Transmission
- variola virus shed during acute infection
- outbreaks in rural area got all age groups
- only kids in urban (frequent exposure)
- monkeypox is relatively rare and less transmissible, but just as serious
Prevention and Treatment
- vaccination is key (but none for other enteroviruses)
- isolation of infected
- resistant to disinfectants
Respiratory Syncytial Virus
- severe in infants and kids, mild URT in adults - infants esp prone -> bronchiolitis and pneumonia
- most common viral thing in infants (2-7 mos), esp bad if premature
- big immunosuppressed adults and elderly
- all infected by age 2, adult
re-infection common
- 1o infection most severe
Opportunistic infections – Fungal
- Candida (oral -> esophagus)
- Pneumocystis carinii (pneumonia - PCP)
- Cryptococcus neoformans (meningitis)
- Histoplasma capsulatum (pneumonia or disseminated)
HCV immunity
- virus undergoes “antigenic drift” within the patient - specific ab's promote the selective propagation of virus with variant antigens
- “Quasi-species” concept.
- positive serology means on-going infection and viremia: not recovery
(+) RNA
- replication: parental (+) -> (-) RNA -> progeny (+) RNA
- gene expression: parental (+) -> mRNA thats translated directly
Human Herpesvirus 6 and 7
Clinical Features
- 6th disease or "roseola" in kids under 2
- high fever and a red rash
- resolves in 3-5 days without complications or sequelae, and most are asymptomatic
- 50% of febrile episodes in infants due to HHV-6
- lifelong protection, so infection in immunocompetent adults is rare
- not part of differential diagnosis
- most related viruses ass. w/ animals or travel, take careful history
Killed vaccine advantages
- can be combined w/ (DPT)
- no mutation
- ok if immunodeficient
- reduces spread of live polioviruses
Respiratory Syncytial Virus
- transmitted by close contact
- aerosolized in large droplets of resp secretions
- infected kids shed for 3 wks
- can stay of surfaces for hrs
- spread in hospitals and daycare is a major problem
- mid-winter to late spring
- handwashing prevents!
Opportunistic infections – Protozoan
- Cryptosporidium (gastroenteritis)
- Toxoplasma gondii (encephalitis)
(-) RNA
- replication: parental (-) -> (+) RNA -> progeny (-) RNA
- gene expression: parental (-) -> (+) RNA that acts as mRNA
Human Herpesvirus 6 and 7
Properties of the Virus
- replication & structure like other herpesviruses
- icosahedral capsid and spiked envelope
- latent after 1o infection
- 1 case of virus-associated hemophagocytic syndrome (VAHS) from reactivation - prominent phago of BCs in bone marrow and LNs
Prevention and Treatment
- vaccination for lab workers handling it
- eradication worked b/c humans only reservoir, 1 serotype, all symptomatic, predictable epidemics recovered patients recognized by lesions
- vaccine very stable when dried and vaccinees marked by vaccination scar
- encodes a (TK) that does not (P) ACV so ACV not effective
HCV epi
- humans reservoir - ~1%
- blood-borne pathogen - ~80% prevalence in IV drug users
- drugs, sex, childbirth, transfusion
- blood banks now routinely use serology and an additional RT-PCR test
- RF;s tattos and piercings
- Sexual and vertical transmissions occur less frequently than with HBV
Killed vaccine disadvantages
- low % develop Abs, so repeated boosters neede
- no intestinal immunity
- expensive
Respiratory Syncytial Virus
- treat severe kids w/ humidified O2, bronchodilators and assisted ventilation
- IV IG in high risk cases
- no vaccines, but live attenuated being tested
- hard to make infant vaccine b/c of maternal antibody and the immune immaturity
Opportunistic infections - Bacterial
- Mycobacterium tuberculosis (pneumonia and/or disseminated)
- Mycobacterium avium complex (MAC, disseminated infection, fever)
- higher susceptibility to common infections
Parainfluenza Virus
- (-) sense ssRNA
- virion-associated RNA polymerase
- replicate in the cytoplasm
Human Herpesvirus 6 and 7
- respiratory route - oropharynx ⇒ many cell types
including lymphocytes (esp CD4), Ms, epi and endo cells
- a tiny fraction of these cells become infected during childhood roseola
- replication: parental dsRNA -> (+) RNA -> progeny dsRNA
- gene expression: parental dsRNA -> (+) RNA that acts as mRNA
Properties and Replication
- reovirus family, 11 pieces of dsRNA, so high rate of reassortment
- groups share cross reactive Ags (A, B, C in humans, A in US)
- reassortment w/in groups
- 3 layer icosahedral w/ spikes (must be cleaved to infect)
- cytocidal, replicate in the intestinal epi cell cytoplasm
HCV diagnosis
- Use ELISA for Ab's
- RT-PCR for viral RNA is now available
Live polio vaccine advantages
- humoral and intestinal immunity (like natural)
- immunity lifelong
- oral, works quickly
- relatively inexpensive
- uses of continued cell lines, no contaminants
Opportunistic infections – Viral
- cytomegalovirus (retinitis)
- herpes simplex virus (mucocutaneous lesions)
- Epstein-Barr virus (oral hairy leukoplakia, lymphomas)
- varicella-zoster virus (shingles)
Parainfluenza Virus
- encode a hemagglutinin / neuraminidase (HN) glycoprotein spike that binds sialic acid to attach and enter - high [sialic acid] in URT and LRT
- viral genome transcribed and
nucleocapsids assemble in cytoplasm and bud through PM
- encodes an (F) spike and forms syncytia
Human Herpesvirus 6 and 7
- transmitted by salivary droplets
- requires close contact
- infection is universal
- usually presents in infants soon after maternal Ab waned
- most subclinical or febrile illnesses without the rash
reverse transcriotion
- ss(+)RNA -> (via RT)
- (+)RNA and (-)DNA -> (via RNase H)
- ss(-)DNA -> (via RT)
- dsDNA
- ingested (fecal-oral) -> viruses replicate in the columnar epi -> villi lose the epi cells -> malabsorption -> diarrhea
- glycoprotein 4 may be enterotoxin -> diarrhea
- die from dehydration
- no residual damage if cleared of virus
HCV treatment
- No vaccine
- No hyperimmune serum
- IFNα licensed for therapy experience is mixed - can achieve suppression of viremia
- new aggressive combo is interferon (injections) + ribavirin (oral) for 48 weeks -> ~40% have non-viremic with normal serum ALT esp for Genotypes 2 and 3
Live vaccine disadvantages
- may mutate -> neurovirulence
- spreads to other persons and environment
- problem if immunodeficient
- monkey testing
- AIDS-defining illness in healthy person - then do western blot
- test positive for anti-HIV-1 Abs - then count CD4+ T and level of viral RNA
- flu-like symptoms from acute HIV-1 - common symptoms so consider risk factors – no Abs but plasma RNA
- After a known exposure –
- After birth of a baby to an HIV infected mother - monitor for Abs or plasma RNA for 6 months - some starts administering therapy anyway
Parainfluenza Virus
Clinical features
- 2nd cause of LRT in kids
- the most common cause of croup in kids (esp type 1)
- non-croup infections present as a hoarse cough w/ fever which resolves in 2-3 days
replicating the dsDNA from RT
- dsDNA in nuc -> (via host DNA dep RNA poly II)
- mRNA in cyto -> (via RT and RNase H)
- dsDNA in cyto
Clinical Signs
- subclinical to fatal diarrhea
- infants asymptomatic, maternal antibody
- severe almost exclusively seen in the 6-24 months, as later infections are mild (unless immunocomp, but not big in HIV)
- asymptomatic incubation for three days after vomiting
- diarrhea begins later but then continues for up to a week
- give supportive fluid therapy to resolve
Human Herpesvirus 6 and 7
clinical presentation
HBV genome
- circular pdsDNA, w/ 4 overlaping ORFs w/ no non-coding bases
- 2 in-frame start codons -> Pre C, the signal peptide, is cleaved within Pre C near the carboxyl terminus of C -> HBe
- Viral polymerase has priming domain, RTase, & RNase H and does RT w/in nucleocapsid
- X gene encodes regulatory protein (not involved w/ viron
JC virus
- PML, a progressively fatal, neurodegenerative disease
- due to SV 40 ('the vacuolating agent') – maybe from contaminated OPV vaccine
- Inclusion bodies seen in brain
- 1-10% of AIDS patients
- distantly related to SV 40
- inhibitors include Nucleoside analogs (AZT, 3TC, ddI, ddC) are chain terminatorys - Non-nucleoside RT inhibitors (NNRT) bind RT to inactivate - Protease inhibitors - make sure its strong, wont develop resistance (use combos), and is tolerated
- if 50 copies/ml of plasma, probably no progress or resistance - AZT, 3TC and the protease inhibitor indinavir usually will do this
- if suppression is incomplete, resistance more probable
- for NNRTIs, a single mutation can do resistace – more mutations needed for protease inhibitors
- treat opportunistics normally, except Pneumocystis pneumonia, Toxoplasma encephalitis and Mycobacterium avium - give prophylactics if CD4+ below 200
- most pts survive until T is at 50
- promising alternative therapy is CD4+ T cell production with IL2 – also maybe bone marrow transplants
Parainfluenza Virus
- gets epi of the pharyngeal and nasal mucosa
- spread from cell to cell by fusion then spread to the epi of the larynx and trachea
- resulting inflam -> croup
- restriction to RT b/c host cell proteases cleave the viral fusion protein - w/out this, virions cant infect other cells
WIN compounds (for Rhinoviruses)
- 108 unique serotypes -> continued re-infection
– most use same docking receptor (ICAM-1)
- drugs designed to specifically bind this and prevent entry
- detection of rotavirus (EM), or viral antigen (ELISA or PCR)
Human Herpesvirus 6 and 7
- no antiviral therapy yet
- but Ganciclovir (GCV) has been via IV to suppress HHV-6 replication in lifethreatening
CNS infections in bone marrow recipients
- more sensitive to GCV than ACV but GCV has more toxic side effects
- no vaccine, but most newborns have maternal Ab
- most infants seropositive by 13 months
HBV structure
- the HBcAg is capsid protein - HBe is similar but distinct
- 3 in-frame start codons make Surface/viral envelope - L (large) M S envelope proteins
- Mosly S, but most induced anti-HBs antibody is directed at epitopes in S, but can bind to all 3
- Most HBs in blood is small & spherical w/no nucleocapsid - 1st discovered “Australia ag” - not invecious, sub-unit vaccine idea
- virion aka Dane particle; found at lower []s than HBs
BK virus
- isolated from urine of pt after renal transplant
- in 50% of patients after bone marrow transplantation
- distantly related to SV 40
- 750,000 and one million in US, 36 million in the world – 3rd world bad
- Worldwide spread sustained by heterosexual transmission
- in US, main spread is from homosexuals and IV drugs - esp bad in coastal cities – migration to rural
- leading cause of death in the US among 25 to 44 year-olds
- two related variants (HIV-1 and HIV-2) - 1 is more widespread and pathogenic, 2 is mainly in western Africa
- virus load is high early and late, low in between
- concurrent STD infections increase risk
- 15 30% vertical transmission (in utero and at birth) - AZT decreases chance
- 1 in 300 in sharing needles, 90% in blood transfusions
Parainfluenza Virus
- nasal secretory IgA Abs better than serum Abs
- only Abs to HN and F have been shown to neutralize virus
HBV replicating the product from RT
- pdsDNA ->
- dsDNA -> (transciption)
- m(+)RNA -> (RT)
- pdsDNA
- major cause of severe diarrhea everywhere
- mainly in kids under two in cooler months
- first appears in the SW then sweeps NE
- infection from as few as 10 virus particles
- 48 hour incubation, but shed at high levels through clinical phase
- subsequent infection subclinical from childhood immunity – mild if exposed to a lot
- Aerosol and formite spread
- resistant to inactivation - can retain infectivity for seven months at RT
- frequent nosocomial infection
Parvovirus B19
Clinical Features
- 5th disease (age 1-5 years)
- "slapped-cheek" rash and rash on the trunk w/ low fever
- adults asymptomatic or have arthralgia then flu-like
- if hemolytic disorders -> transient aplastic crisis, from viral impact new erythrocyte prod, combined w/ the reduction in existing ones
- can infect in utero
- persistently viremic infants
w/ severe anemia, so transfusions
- can cause death (hydrops fetalis)
- Papovavirus family
- naked, icosahedral virions
- circular dsDNA
- from SV40 - in 40% of tumors in non-Hodgkins lymphomas and brain and bone tumors and mesotheliomas – contaminated polio vaccine?
Prevention Strategy/Vaccine
- probability of STD spread determined by # of partners, likelihood that partner is infected, transmission conditions
- not all virus-containing blood has antibodies (during acute infection but prior to seroconversion)
- Factor VIII and IX clotting factors are now heat treated to inactivate virus
- immediate AZT treatment after exposure
- No vaccine due to extreme sequence variability - must try to attain sufficiently high levels of protection to block an initial infection (since body cant rid itself of it) - most vaccines increase immunity for a subsequent infection
HBV viral replication
- gapped virion DNA is completed -> to nucleus -> covalently closed circular duplex DNA (ccc DNA) that exists as a plasmid
- transcribed by host DNA dependent RNA polymerase II
- Subgenomic mRNAs synthesized for protein synthesis
- a genome-sized replicative RNA (pregenome) is synthesized
- pregenom packaged into HBcAg
- viral polymerase protein packaged (primer + RTase + RNaseH)
- RT in cytoplasm occurs
- This creates a nucleocapsid w/ dsDNA (and not RNA)
Human T Cell Leukemia Virus Type I - HTLV-I
Viral Properties and Replication
- causes adult T cell leukemia (ATL)
- envelope – one of its glycoproteins does entry into the cell – target for neutralizing Abs
- carries several viral enzymes for replication
HIV and HTLV replicating the prodcut from RT
- ss (+) RNA -> (via RT and RNase H)
- ds DNA -> (via DNA dep RNA pol II)
Treatment and Prevention
- fluid replacement
- vaccine should prevent severe diarrhea in first 2 years (most critical)
- there was a failed vaccine that was withdrawn
Parvovirus B19
Properties of the Virus
- typical parvovirus
- small, no enveloped icosa.
- 1 molecule of +,- ssDNA
- replication and assembly in the nucleus during S phase
- uses host enzymes, no integration into host DNA
- replicate in nucleus - do NOT encode a viral DNA dependent DNA polymerase;
- use host DNA dependent DNA polymerase for genome replication
- uses host DNA dependent RNA polymerase II for transcription
- progeny virions assemble in cell nucleus
- excess mortality
- results from novel A virus
- 1918, 1957 and 1968.
- confined mainly to elderly and ill
HBV clinical course
- 1o infections asymptomatic
- In children, mostly asymptomatic w/ high rate of chronic carriage
- if immunosup, always asymptomatic and persistent
- longer incubation prior to symptoms than HAV or acute HCV
- Chronic may develop, CPH, CAH, PHC - staging by biopsy
- CAH → cirrhosis → PHC 2-30+ years
- Antigen-antibody complexes ⇒ polyarteritis, glomeru
- subclinical ⇒ fatal acute fulminant
- anti-HBeAbs is a good sign, along w/ viremia, less replication in liver, lesser rate of immune-mediated damage to liver
- formerly called RNA tumor viruses
- have RT and RNase H to copy RNA into DNA intermediate
- integrase inserting viral DNA into the host chromosome
- large precursor proteins assemble the particle then are cleaved by protease
- piconovirus WIN
Norwalk Agent
Properties and Replication
- calicivirus, naked, (+) sense ssRNA
- fastidious in their growth requirements, replicate poorly in cell culture
- humans only reservoir
Parvovirus B19
- narrow specificity for host cells in bone marrow, fetal liver or heart
- killing host cells (erythropoeitic cells)
- causes high titer viremia w/ bone marrow depression thats
short-lived, ending due to the development of Ab
- rash and adult rheumatic syndrome due to immune-complex formation
- infection -> lifelong immun.
- only in immunosuppressed -> inapparent, cryptic infection
- transmitted via respiratory route
- host cells are killed by viral cytolytic infection
- cannot manifest transformation phenomenon
- can be transformed to neoplastic growth in non-natural cells
- pleomorphic
- smaller than paramyxoviruses
- 8 segments of (-) polarity ssRNA
- helical nucleocapsid w/ envelope
- viral RNA polymerase is packaged within the virion
- 2 proteins on surgace, hemagglutinin (H) and the neuraminidase (N)
- first identifies as H1N1, but H2N2 and H3N2 also came along (so H1N1 gets younger people b/c older have immunity
HBV Pathogenesis
- regulates replication level in each hepatocyte so cell isn't overstressed - no cytopathology is apparent
- replicates to very high levels in HIV pts
- For HBV caused PHC, 80% of tumors have integrated HBV DNA
- low level of infection at specific extra-hepatic sites
- a mutant type is more fulminant and has HBe negative phenotype and serology
Clinical Features
- low virus load w/ seroconversion shortly after infection
- malignant infected cells are mature T cells, w/ multilobed nucleus
- characterized by high WBCs, infiltration of CNS and rapidly fatal course
- can cause immunodeficiency, leading to opportunistic infections
get influenza A M2 protein (to block its role as an ion channel) and prevent nucleocapsid release
Norwalk Agent
- villi of the SI broaden and become blunted
- epithelial mucosa remains intact, but malabsorption -> diarrhea
- nausea and vomiting due to affected gastric motor function
Parvovirus B19
- infected spreading virus w/in 5-6 days of infection until sufficient Abs (10-14)
- widely disseminated in community-wide epidemics via school-age children
- can survive pasteurization of blood products
Influenza A
- in both humans and animals
Herpesviridae family
- herpes simplex (HSV)
- varicella zoster virus (VZV)
- cytomegalovirus (CMV)
- Epstein-Barr virus (EBV)
- HHV 6 and HHV 7 (roseola)
- HHV 8 (Kaposi sarcoma associated virus)
- monkey B virus (serious neurotropic virus for humans)
HBV Immunity
- specific CTLs, directed probably at HBc and/or HBe Ags
- Persistent infection can resolve, along w/ anti-HBsAbs so liver damage ends
- act as a cofactor in tumor formation
- first there is transient polyclonal outgrowth of cells w/ integrated DNA
- inappropriate expansion may allow other genetic changes
- viral expression is difficult to detect, which suggests that viral gene product is not required to maintain the transformed state and its role is early
- if virus-encoded tax transcriptional activator protein increased the expression of IL2 and its receptor, cell growth would be chronically stimulated – window for genetic mutations that contribute to cell growth and malignancy
- associated w/ p53 mutation and tropical spastic paraparesis (TSP), a myelopathy – SC inflame that leads to partial paralysis
get influenza A M2 protein (to block its role as an ion channel) and prevent nucleocapsid release
Norwalk Agent
Clinical Manifestations and Diagnosis
- 24 hour incubation, 24-48 hours
- nausea, vomiting (in adults), diarrhea (in kids)
- no immunity if previous exposure, maybe due to different serotype or genetic # of virus receptors
Parvovirus B19
- clinical presentation
- isolated cases are commonly misdiagnosed as measles, etc.
Influenza B
- only human, preferentially kids
- Reye's syndrome is a complication w/ aspirn
- HA and NA relatively stable, genetically
Clinical Features
- Primary Disease usually asymptomatic (esp if < 10 YO) - if symptoms, gingivostomatitis, with vesicular eruptions on mouth -> ulcerative lesions - 2-3 weeks
- latent infection in sensory neurons then reactivated disease from stress - prior to episode, often altered sensation of area, then vesicls 1-2 days later – fewer lesions than 1o and on mucocutaneous borders - asymptomatic shedding common
HBV primary infection
1 - acute episode - strong immune response → clearance, recovery, no persistence, lifelong immunity (anti-HBsAb)
2 - acute episode, intermediate immune response → persistent infection → chronic liver disease
3 - no acute disease, asymptomatic → persistent infection (healthy carrier) → tolerance erodes → chronic
liver disease
- In healthy carriers no activated (HBV specific) CTLs. CTLs seem “anergic”.
- no treatment for 1o (usually inapparent)
- chemo leads to short term remission in 50%
ACV acyclovir
(analog of dG) for HSV, VZV
chain terminator
Norwalk Agent
- often the diagnosis in GI outbreak if others have been ruled out, more than 50% are vomiting, its an epidemic fashion, and its for 24-48 hrs
Parvovirus B19
- typically not treated
- transient aplastic crisis is readily treated by blood transfusion
HBV epi
- 400 million carriers, esp in
Asia, sub-Saharan, Aleuts, Am. Indians, and Polynesians
- intermediate prevalence in Mediterranean countries
- lower prev in western Europe and Caucasian Americans (mainly via STD)
- moms can pass on so screen
- teens and college at most risk
- highest titer in blood, but in spit and semen
Influenza C
- infects humans and swine
- causes sporadic URT illness, sometimes LRT
Clinical Features
- Primary Disease usually symptomatic - painful, vesicular lesions on the genitals -> pustules and ulcers - systemic infection common
- reactivated Disease is milder - 1o was severe, recurrences more frequent - asymptomatic shedding common
- via semen, milk, and blood - Male to female common, female to male rare
- Vertical (via breast feeding) is the main means
- low lifetime risk if infected of developing ATL or TSP
- very low level throughout the world
GCV ganciclovir
(analog of dG) for CMV
chain terminator
Norwalk Agent
- not big in infantile diarrhea
- outbreaks in schools, institutions - gets adults and school age children
- epidemics from contaminated shellfish, food, or water
- 1/3 to 2/3 of GI epidemics
Clinical Features
- serogroup A and B
- can be severe in both kids and adults
- may present as isolated cases or as an epidemic
- infections of NS and URT, LRT, rashes, myocardial disease and conjunctivitis
HBV Diagnosis
- serology
- if acute, rise in HBs Ag in acute infection then gradual decline, (immune response)
- window period is when HBs Ag has disappeared, but anti-HBs Ab hasn't appeared - only sign is anti-HBc antigen
- if chronic, the HBsAg rise during acute is maintained - accute can be un-noticed
- HA binds sialic acid to enter cell, then HA cleaved to uncoat – the easier it is to cleave, the more virulent
- NA cleaves sialic acid to do cell-to-cell spread
- replication in nucleus
- virus polymerase error prone
- individual nucleocapsids encapsidate each segment, then they assemble at random into virions and bud from PM
- need 8 segment, but as many as12-15 incorporated to ensure
- if 2 different strains replicate -> reassortment and new combos (esp w/ A) – bad!!
HSV in Pregnancy
Clinical Features
- vertical transmission of HSV-2 during delivery (asymptomatic shedding)
- recurrent disease is much less risky because of the reduced shedding of the virus
- in utero cases systemic, with high mortality
- Vaccination of women would work
- donated blood is screened
AZT azidothymidine/zidovudine
(analog of dT) for HIV
chain terminator
Norwalk Agent
Treatment and Prevention
- oral fluid replacement
- Pepto-Bismol (bismuth salicylate) to reduce symptoms
- just be sanitary to prevent
Serogroup A
- herpangina - fever, sore throat, vesicles in oropharynx; acute onset
- hand foot and mouth disease w/ ulcerative vesicles on
buccal mucosa, and vesicular rash on hands and feet
- aseptic meningitis - typically, uneventful recovery
- epidemic conjunctivitis - some forms hemorrhagic
- infantile diarrhea
HBV vaccination
- subunit vaccine is recombinant HBs Ag
- universal vaccination of newborns - birth, 1 month, 6 months
- if job has infection risk -
immediate, 1 month, 6 months
- effective post-exposure if given within one week
- neonates of a carrier mom immediately given HBIG and a vaccination course
- exposed can get passive immun.
Clinical Features
- 3-5 day recovery, some may develop pneumonia (will be what kills you)
- asymptomatic to fatal primary influenza
- clinical onset occurs with a sudden rise in temperature within 1- 4 days post-exposure
- correlation b/t level shedding and severity
- coughing possibly for months, as ciliated epi is re-established
Acute Necrotizing Encephalitis
- most common cause, high mortality
- usually in immunocompromised
Human Papilloma Virus - HPV
Properties and Replication
- naked, papovavirus family – circular dsDNA
- 70 strains w/ strict epithelial cell tropism
ddI dideoxyinosine/didanosine
(analog of dA) for HIV
chain terminator
- do acute respiratory syndromes and epidemic keratoconjunctivitis
- 2 serotypes (of dozens) associated with gastroenteritis
- really only do nosocomial diarrhea in young children
Serogroup B
- pleurodynia - acute chest pain and fever - 2-14 days
- myocarditis and pericarditis - acute and chronic forms (due to CTL response)
- neonatal infection can be inapparent to fatal - resp and CV involvement - from the nursery or transplacentally
- associated with juvenile diabetes
HBV treatment
- IFN for non-Asians
- Lamivudine (3TC)
- Adefovir
- Lamivudine + penciclovir
- cant use AZT (conjugates in liver) or proteases (doesn't encode protease)
- gets cells lining the air passages
- replication -> desquamation of ciliated epi
- if 2o bacterial infections, harder to clear it -> bacterial pneumonias from step, staph, and Haemophilus
- 1o viral pneumonia is less common, usually old or CP disease -> hypoxema and death
- Reye’s syndrome (cerebral edema / degen of liver) in kids w/ B
Herpes simplex Keratoconjunctivitis
- second to trauma as a cause of corneal blindness in the U.S.
Human Papilloma Virus - HPV
Clinical Features and Pathogenesis
- cause epithelial dysplasias (i.e., warts)
- via viral contact with MMs or traumatized skin
- some cause common warts, others associated w/ carcinomas
- in the cancers the viral genome is frequently integrated breaking the circular DNA so that an important viral regulatory protein is not produced -> viral genes E6 and E7 to be produced at a higher level -> inactivating the cell’s tumor repressor genes, Rb and p53
3TC lamivudine
(analog of dC) for HIV, HBV
chain terminator
Properties of Virus
- typical enteroviruses
- naked, icosahedral - 1 molecule of (+) RNA
- replication confined to the cytoplasm like polioviruses
- treats HBV
- acyclic nucleotide similar to dAMP - ring more flexible
- converted first to mono then to di-phosphate which is dATP analog
- terminates chain of HBV DNA synthesis
- great unconquered epidemic
- person to person via droplets
- Antigenic Drift - high mutation rate (since RNA) - HA Ab correlated with protection against disease so changes in HA protein -> new strains that can escape neutralizing Ab - antigenically new strains every 2-3 years
- Antigenic Shift – (1) in A zoonotic allows reservoirs for propagation of viruses, more H and N possibilities – (2) individual cells may be infected w/ different virus strains – (3) segmented nature of genome
- large dsDNA
- icosahedral capsid surrounded by the tegument in envelope
Human Papilloma Virus - HPV
- find cervical dysplasia in paps
- PCR to identify a specific strain
- (analog of dAMP) for HIV, HBV
- undergoes two sequential (P) rxn by host kinases to produce the active drug, adefovir diphosphate (analog of dATP)
replicates in OP and GI lymphoid tissue ⇒ the RES ⇒ skin, myocardium and the central nervous system
- Supportive treatment for relief - acetaminophen for aspirin reduces risk of Reye’s syndrome from B
- amantadine (rimantadine) Anti-Viral Drug - inhibits of uncoating – gets A if given w/in 28 hrs – shortens course
- Neuraminidase Inhibitors (A and B) - binds sialic acid on NA
- Prevent w/ prophylactic amantadine (for A only)
- in nucleus
- transcription by host DNA dependent RNA polymerase II
- replication by virus-coded DNA dependent DNA polymerase
- envelope and maturation in cytoplasm
- 3TC, treats HBV
- blocks viremia, but most cases rebound in post-drug setting
- long term benefit uncertain
Human Papilloma Virus - HPV
- via direct contact - more common in older children and young adults
- not highly contagious, epidemics are rare, but genital warts #1 STD (w/ Chlamydia)
- 2-6 month incubation
- cervical cancer is 1/4 of all cancer in women
- some genital tract HPVs (including the squamous cell cervix carcinoma one) are considered STDs – high # of sexual partners is main RF
Pyrophosphate analog
- fecal-oral mainly, but also
inhalation of droplets
- active infection may block poliovirus vaccine - concurrent enterovirus infections can interfere with replication among each other; one enterovirus infection then dominates
- Currently formaldehyde-inactivated virions from embryonated eggs - 2 doses (1month interval) - induces anti-HA Ab in 85% - immunity short lived
- one dose for adults, 2 for non-immunized kids (4 wk interval)
- WHO network monitors and detects new viruses
- vaccinate old, infants, chronic disorders, and pregnant
- Trivalent vaccine for 2004 - 2005
- FluMist™ - cold-adapted, live-attenuated, trivalent
- Molecular vaccines - appropriate HA Ags in genetically engineered bacteria and live attenuated A and B chimeric viruses
- invades epi -> multinucleate giant cells
- released via exocytosis and cell necrosis
- main pathogenic effect is cell lysis - leaks vesicular fluid between the dermis and epidermis creating the vesicle
Lamivudine and penciclovir
- chain-terminators, treat HBV
- used in liver transplant pts
- drug-resistant strains emerge due to mutations in HBV RT
Human Papilloma Virus - HPV
Prevention and Treatment
- Limiting # of sexual contacts and do regular Paps
- 50% of common skin warts will regress spontaneously
- can do surgical removal, but reoccurrence is common
for HIV - binds directly to HIV RT and inhibits the DNA poly
Diagnosis and Treatment
- can be isolated from stool samples, pharyngeal secretions and vesicular fluids
- serum typed for presence of convalescent antibodies
- no antiviral drugs or vaccines available
- HSV-1 universal, usually before 5
- spread by direct contact with lesions or secretions
- asymptomatic kids are major HSV-1 source
- no animal vectors or seasonal patterns
- sex is HSV-2 source – 20% of females shed asymptomatically
HDV genome
- small, circular ssRNA virus
- no genes for envelope or replicating - replicates only in host cells HBV co-infected
- 1 ORF for HD Ag (internal core protein)
- (-) sense, so unique b/c it does NOT encode RNA-dependent RNA-polymerase
- uses host DNA dependent RNA
polymerase II
Epstein Barr Virus
Properties and Replication
- herpesvirus that gets 90% of the world pop
- linked to B-cell and epithelial malignancies
- can infect B’s in vitro and induce growth in culture
- most cell lines from PBL don’t produce infectious virus – considered “latently” infected
- In nucleus, linear DNA forms the extrachromosomal episome - replicated by host and partitioned to each daughter cell (as long as oriP and EBNA1 are there)
(analog of rG) for RSV, Lassa, HCV – (P) then inhibits rxn w/ rGTP – also act as an immunomodulator
- history and vesicular lesions
- characteristic CPE in tissue culture
- in herpes encephalitis, PCR of the CSF
HDV structure
- RNA formed into a fragile nucleocapsid with the HD Ag
- parasitizes envelope form HBV lipoprotein
- The viral RNA is also a ribozyme - can self cleave, and ligate
Epstein Barr Virus
Clinical Features and Pathogenesis
- 1o usually early in life, frequently by age 3
- largely asymptomatic
IFNs (alpha, beta and gamma)
- cytokines in response to infected cell or RNA
- bind to specific receptors on target cells and induce 'responses' and transcription
– some block RNA and protein synthesis, and others step in the infection process
– for HCV and papilloma viruses
- no vaccine for either form is yet licensed
- acyclovir (Zovirex™), a nucleoside analog – only active in virus-infected cells -> chain termination
- can become resistant from mutations of viral TK that don’t accept ACV
- fortunately, acyclovir resistant mutants are avirulent
- a new subunit vaccine of HSV-2 envelope D is in trial
HDV clinical features
if co-infection with HBV, there is a more aggressive clinical course with higher mortality
Infectious Mononucleosis (IM)
- salivary exchange, then replicates in epi (tonsillar lymphocytes?) -> viremia
- 1st wk - portion of circulating Bs are EBNA (+) and may produce IG and autoantibodies (the heterophile Ab reacts w/ sheeps blood and is used to diagnose)
- imbalance between a polyclonal proliferating and latently-infected B’s VS cytotoxic T’s that would control them
- then there is latent infection in B’s (escapes the cytotoxic Ts)
- virus DNA persists as episome and infection persists for life
- degree shedding varies – may reflect a chronic low grade replication in OP epi cells
Negri bodies
Rabies virus
HDV pathogenesis
- Two infection settings
1) Naive pts get both HBV and HDV simultaneously -> acute episodes of both, first HBV, then HDV -> high, transient viremia
2) HBV carrier gets HDV as a superinfection -> chronic forms of both
Burkitt’s Lymphoma (BL)
- endemic area in Africa, tumors in jaw - kids before two years
- characteristic chromosomal translocation that alters the regulation of c-myc expression so its controlled by IG promoters
- elevated Ab titers to viral Ags, like VCA and EA, preceding the tumor
- All tumors have EBV in all of the malignant cells
Indinavir, Saquinavir, Ritonavir
Protease inhibitors for HIV
HDV immune response
- Acute vs chronic is determined by immune response to HBV
- If the immune system clears HBV from the liver, it also clears HDV
Nasopharyngeal carcinoma (NPC)
- epithelial tumor - in Asia - elevated Ab titers to viral Ags
- viral genome in malignant cells
- other co-factors contribute to cancer development
- latent infection then expression of viraltransforming genes are crucial events
Zanamivir (Relenza)
- Inhibitors of the Influenza A and B
- analog of sialic acid
- Transmission probably like HBV
- In the US, outbreaks in IV drug users who share needles
Hodgkin’s disease (HD)
- if history if IM, 2 to 4X more likely to get this lymphoma which develops from EBV infected cells
- Reed-Sternberg cell (similar to those in IM) is malignant cell
- viral DNA and EBERs commonly found in RS cells
Guarnieri bodies (cytoplasmic)
smallpox virus
HDV diagnosis
- Detect either HD antigen or antibody to HD antigen
Lymphoma associated with immunosuppression
- may develop in patients with congenital immune impairment
- also responsible for most post-transplant lymphoma (PTL)
Nuclear and Cytoplasmic inclusions
measles virus
HDV treatment
- No specific treatment or vaccination
- Vaccination for HBV protects against HDV
- Lamivudine or penciclovir will inhibit HBV RT process, but NOT synthesis of HBs Ag - so they wont affect the course of HDV infection
- IM is characterized mononucleosis (atypical lymphocytosis) and “monospot” test (sheep blood thing)
- malignancies identified clinically in high risk populations
- BL or NPC have serologic responses prior to onset of malignancy
Treatment and Prevention
- latent infections, so antiviral therapy for the viral DNA polys wont work
- IM self-limiting, symptoms vary widely
- no vaccine (it would eliminate ass. Cancers)
- Post-transplant lymphoma treated by reducing immunosuppression and by giving viral-specific cytotoxic lymphocytes
- in cancers, multiple viral proteins for weird growth so immune-mediated therapy and specific molecular therapy directed toward the viral functions will work
Human Herpes Virus 8 (HHV-8)
Virus Properties and Replication
- most recently discovered HHV, discovered in Kaposi’s sarcoma (KS)
- in transformed cell, viral DNA is circular, possibly clonal
- has genes acquired from the host genome
- may induce growth by inducing infiltrating cells to secrete cytokines or by expressing autocrine growth stimulatory molecules
Human Herpes Virus 8 (HHV-8)
Clinical Features and Pathogenesis
- KS not very aggressive - forms multiple skin lesions
- incidence has dramatically increased in HIV patients
- caused by a STD agent, with patterns of appearance, remission, reactivation seen in other herpesviruses
Human Herpes Virus 8 (HHV-8)
- consistently detected in AIDS-associated as well as classical KS
- rarely detected in normal healthy subjects
- sometimes in AIDS lymphomas
- may not be ubiquitous