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115 Cards in this Set
- Front
- Back
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What is HHPV a marker of?
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Sexual activity
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Can HHPV be used to determine if someone has cervical cancer?
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No
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Describe the genome of herpesvirus
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dsDNA
125,000-229,0000 bp (125-229 kb) Circular, around central core of virus |
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Describe the structure of herpesvirus
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Icosahedral symmetry of virus capsid
162 capsomeres Surrounding tegument Env mb derived from nuclear mb by budding |
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Describe the HSV ptn expression
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100 transcripts
70 ORFs Circular genome!! |
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Does this virus have any introns?
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Yes, has 2 copies of LAT gene
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What is LAT?
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Latency ass't transcript
->Spliced transcript |
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What happens to HSV-1 during latency?
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HSV-1 infects nucleus of tissue
LAT is the only gene expressed from virus during latency |
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What do all HHV have in common?
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All have IDENTICAL EM morphology
All are ubiquitous, can infect a majority of all humans All remain latent lifelong and may reactivate |
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What are all the herpesviruses?
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HSV1/2
VZV (HHV3) EBV (HHV4) CMV HHV6/7 KSHV (HHV8) |
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HSV 1/2
Tissue tropism Site of latency Comment |
Tissue tropism: Skin, nerves
Site of latency: Sensory neuronal ganglia Comment: Predominantly labial and genital disease |
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VZV
Tissue tropism Site of latency Comment |
Similar to HSV1/2
Tissue tropism: Skin, nerves Site of latency: Sensory neural ganglia Comment: Chicken pox (Varicella), Shingles (Zoster) |
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EBV (HHV4)
Tissue tropism Site of latency Comment |
Tissue tropism: B lymphocytes
Site of latency: Lymphocytes Comment: Infectious mononucleosis |
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CMV (HHV5)
Tissue tropism Site of latency Comment |
Tissue tropism: Multiple tissues
Site of latency: Multiple tissues Comment: Multiple syndroms: perinatal infections, severe and reccurent diseases in compromised hosts |
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HHV6
Tissue tropism Site of latency Comment |
Tissue tropism: T lymphocytes
Site of latency: Lymphoid Comment: Exanthem subitum (Roseola) -->Children infected by mother's salvia |
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HHV7
Tissue tropism Site of latency Comment |
Very similar to HHV6
Tissue tropism: T lymphocytes Site of latency: Lymphoids Comment: Exantham subitum, cause of reactivation of HHV6 |
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Kaposi Sarcoma (HHV8)
Tissue tropism Site of latency Comment |
Tissue tropism: Skin, B lymphocytes
Site of latency: Lymphoid Comment: Ass't with KS, HIV-related B lymphomas and other proliferative skin disorders in immunocompromised patients |
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Describe similarities/differences btw HSV-1/2
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Serologically distinct mb glycoptns
Similar manifestations when infecting identical sites Used to have different but now converging epidemiological patterns |
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What kind of disease does HSV-1 mostly cause?
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Mostly labial infections, ocular keratitis and encephalitis in adults
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Where does HSV-1 mostly go when it infects someone?
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Brain
Head Neck |
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What type of infections does HSV-2 usually cause?
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Urogenital infections
Whitlow (hand infection) --> about the same rate of infection for HSV-1 Meningitis (adults) Neonatal infections |
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Where do most HSV-2 infections occur in the body?
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Tends to move to the CNSq
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What is happening now to HSV1/2 infections?
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Getting more cross btw HSV1/2 infections
HSV1 also starting to infect urogenital tract HSV2 also starting to infect the labia |
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What does H. labialis infecy?
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Labia
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What proportion of the population is infected with HSV-1/2?
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30-100% of population infected by age 5
30-50% of middle class kids 80-100% of poorer populations |
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Describe HSV1/2 primary infection
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Usually asymptomatic
BUT, if it does cause symptoms, usually causes severe ones (severe gingivostomatitis) |
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What is the incubation period of HSV1/2?
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2-12 days
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What parts of the body can be infected by HSV1/2?
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Eyes, hands, other skin
-->can be infected de novo or by autoinoculation |
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What effect does this virus have on patients that aren't immunocompromised?
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Usually no serious sequelae
Treatment is optional |
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How long does it usually take for vesicles to heal?
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3-7 days
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What is cirrhiosis?
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Disturbing continuity of epidemal barrier to infection
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What happens in neonatal infection?
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Babies develop inseminated infection, spreads to visceral organs and the brain
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What kind of disease is herpes?
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STD
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What causes most of the disease?
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Reccurent infection
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What is a recurrent infection?
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Occurs in the same site as primary infection
Latency occurs in sensory ganglia |
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What causes is reactivation usually associated with?
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concurrent infection, fever
Stress, menses, exposure to UV light |
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Are small quantites of virus shed asymptomatically?
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Yes, periodically
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What is VZV?
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Varicella zoster virus
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What are teh 2 distinct types of VZV infection?
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Varicella
Zoster |
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What is varicella?
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Chicken pox
A Primary infection Always disseminated |
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When does chicken pox occur?
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Happens at the initial infection
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When does zoster happen?
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Reactivation (never happens in primary infection)
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Wat is Zoster?
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Shingles
-> Local recurrence of latent infection |
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Where does virus enter its latency?
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Sensory neuron in the ganglia
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How long does it take for reactivation?
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Years/decades after 1ry infection, get recurrence in a single sensory nerve ganglion
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Where does reactivation of VZV usually occur?
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Usually only on 1 side
Localized area of infection |
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How is VZV transmitted?
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Vesicle fluid and respiratory secretions
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Hoiw long is the incubation period of VZV?
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14-15 days
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Where is VZV highly contagious?
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In homes and schools
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What happens in the absence of vaccination?
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Primary varicella occurs in 50-80% by age 6
85-95% of adults are seropositive Among seropositive adults: only 80-90% have a history of known varicella ->Many cases are mild/inapparent |
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What generally happens if you catch acute chicken pox?
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1ry infection, recovery and seropositivity: provides absolute immunity to reinfection
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What are subsequent manifestations of this virus in ppl who are acutely infected?
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It is reactiavation of latent virus from sensory ganglia
-->NOT reinfection |
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What are the symptoms/manifestations of varicella?
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Fever, chills, myalgia
Rash can come after crops of vesicles ->Usually resolves over 7-14 days -Illness usually mild in children -Not uncommon for adults to have >1000 vesicles Can get progressive varicella in immunocompromised -->lung/brain/liver: pneumonia, meningoencephalitis, hepatitis -Rare in healthy ppl, but can happen in 10-20% of pregnant women |
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Describe the manifestations of zoster
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Localized recurrence in the nerve cell in unilateral sensory dermatone
2-3 days of pain prior to onset of visible skin lesions Pain, itch and visible vesicles Oncidence and severitiy proportional to age? |
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What is the healing time for zoster?
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5 to 30+ days
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Why is there pain several days before the onset of skin lesions?
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Same reason as for chicken pox because the virus is localized to nerves
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Where does zoster stay latent?
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In the nuclei of cell bodies of the sensory veins of posterior root ganglia
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Where can zoster reactivation take place?
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Either side of the spinal cord
3 divisions of the face |
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Where does the sensory of the face come from?
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Not from spinal cord
->comes from a cranial nerve, the Trigenial nerve ->Has a ganglion anterior and superior to the ears |
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What can varicella do to the lungs?
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Causes progressive varicella pneumonia
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What is the difference btw small pox and chicken pox?
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Difference in distribution
Small pox: densest amt of vesicles on face and limbs (feet, arms, legs) Chicken pox: most clusters are on the face and torso Can also have vesicles on mucous mb |
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Describe CMV infection
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Infection is ubiquitous but nearly always inapparent
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What increases transmission of CMV?
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Inc exchange of body fluids
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Describe the acquisition of CMV
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1) Perinatal:
30-50% of infants infected during 1st yr of lige, probably by vertical transmission MV present in maternal blood and breast milk of sero+ mothers 2) Reproductive age: Additional 20-50% infected during 2nd and 3rd decades of life CMV is present in saliva and genital secretions |
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Where can infectious virus be present in asymptomatic seropositive individuals?
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Urine
*saliva WBCs *Semen/vaginal secretion Breast milk Cerebrospinal fluid Can also be present in many tissues despite the presence of serum Ab |
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How does CMV escape serum Ab?
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CMV is mostly intracellular, not extracellular
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What is symptomatic CMV disease?
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Rare congenital disease
Predominantly occurs in immunocompromised patients ->Can be new infection/reactivation during post-transplant immunosuppression Syndromes vary: fever, hepatitis, pneumonia in transplant patients -Retinitis, pneumonia, esophagitis and disseminated infections common in AIDS patients Can also infect the eye |
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Doe sCMV lung infection look different than varicella lung infection?
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Yes
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Whhat is EBV?
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Kissing disease
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What is the distribution of EBV in North America?
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90-95% of the population is seropositive by age 30
very ubiquitous 50% are positive by age 5 remainder convert during 2nd and 3rd decades of life |
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How is this virus shed?
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Oropharyngeal (saliva) shedding of virus
Sero+ adults: 10-25% Recent transplant recipients: 50-75% Acute infectious mono: 50-100% Acute leukemia/AIDS: 85-100% |
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What is infectious mono?
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A SYNDROME, not a disease
->Is a gp of symptoms |
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What are the symptoms of mono?
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Fever
Sore throat Lymphadenopathy |
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What are the signs of mono?
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Splenomegaly
Hepatomegaly Palatal enanthem (rash on mucosal surfaces) Jaundice Rash |
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Are all infectious mono caused by EBV?
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No, can also be caused by CMV
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What happens in mononucleosis?
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Pronounced increase in mononuclear cells (atypical lymphocytes)
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How can you test for mono?
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Develop transient reactivity on the mono test/mono spot test: 90-95%
->need to develop a specific and permanent anti-EBV Ab test which the mono test doesn't test for |
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Describe the mono test
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Mix patient's serum with horse RBC
Heterophile during acute stage of infectious mono, makes Abs that react vs horse RBCs When you get better from horse RBCs, stop making these Ab |
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Can EBV be oncogenic?
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Yes
ex: Marek's disease virus of chickens (infectious lymphoma can be preventedby vaccination) African Burkitt's lymphoma Nasopharyngeal carcinoma in orientals -->Both are consistently positive for episomal EBV DNA and EBV-specific Ag |
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What role does EBV play in these carcinomas?
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EBV is necessary but not a sufficient condition for the development of malignancy
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What else is required for EBV infection to be malignant?
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Genetics (African/oriental)
Co-existent malarial infection |
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What happens to B and T cells during infectious mono?
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Significant polyclonal increase in both B and T lymphocytes
-Early mono: B/T ratio --> 4:1 -Late mono: B/T ratio -->1:4 (reversal of ratio) |
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Why is there an early excess of B cells?
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Get polyclonal hyperglobulinemia
-Causes non-specific polyclonal activation of Ig synthesis that leads to presence of heterophile, that is the basis for the mono test (why we react to horse RBC) |
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What happens to EBV infected and transformed B cell in vitro?
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They are immortal
-->Used to generate human monoclonal Ab |
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Why is there a late excess of T cells?
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Increased # of cytotoxic lymphocytes directed vs EBV infected B cells
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What is EBV-induced infectious mononucleosis?
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Essentially a polyclonal B cell lymphocytic leukemioa lymphoma which is usually controlled by our IS
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What happens when EBV infects ppl with severe T cell defects?
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Sometimes manifests as a progressive B cell proliferative disease which behaves as do lymphomas
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Describe KSV induced oncogenesis
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Kaposi;s Sarcoma
Vascular neoplasm Low endemic incidence ->Very low grade, localized skin lesions Increased incidence in AIDS patients and immunocompromised Also ass't with Lymphomas |
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Describe the HSV life cycle
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1) Glycoptns on cell surface bing to receptors on target cell
2) Virus mb fuses with host cell mb 3) Releases icosahedral nuclear capsid 4) Capsid moves along elements of the cytoskeleton to nuclear pores, where DNA unfolds in the nucleus 5) New nucleosome made in nuc after virus has left and new viral ptns have entered the nucleus 6) New nuclear capsids bud through the mb, intothe ER, transported into the Golgi, up to the cell surface and released |
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Describe what happens in HSV infection
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Initial ass't is non-specific btw proteglycans pf cell surface and virus glycoptn C (gC)
fusion with cellular mb Viral capsid migrates to nuclear pores alonf cellular mt utilizing cellular transport machinery Viral DNA injected through pore while capsid ptns remain in cytoplasm Then get fusion with the cellular mb follows ->action of a number of viral glycoptns including gB/H/I/L -Viral capsid with tegument ptns migrates to nuclear pores along cellular microtubules utilizing cellular transport machinery -viral DNA injected through pore while capsid remains in cytoplasm |
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Describe the encapsidation and release process
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Procapsid ptns are assembled around scaffolding ptns that are then digested away
Empty capsidss incorporate DNA by means of the action of cleavage/pckging ptns Filled capsids ass't with tegument ptns and become enveloped during migration through the nuclear mb Glycoptns are transported in vesicles to the nuclear of plasma mbs Viral capsids ass't with virus modified mb which interacts with virus encoded matrix ptns Final release of the enveloped virions from the cell involves the virus being incorporated into exocytotic vesicles, then released from the cell as free infectious viru |
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Describe what happens in primary infection
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Nc get into peritoneal sensory nerve fiber of the nerves that are entering the area around the mouth
Nc migrate retrograde alonf the axon to the nuclear pore, neuronal cell body nucleus in the gagnlion dsDNA (round) then infects and remain latent in the nucleus of the neurons |
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Describe what happens in recurrent infection
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Reactivation
Stimulated to T early and late stage RNA Make ptns, capsid and scaffold Migrate back down the axon Get released near site of original infection |
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Where does latent infection and reactivation take place?
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In sensory neurons
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What happens as the virus replicates in the neurons?
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Some are destroyed, but most are refractory to it during 1st infection
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What happens to the viral genomes in latency?
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They become associated with host histones and persist as mini chromosomes
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What HSV transcript do some latently infected neurons express?
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LAT
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Where is Lat encoded?
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Repeat regions of the genome
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Does LAT encode ptn?
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No, it is a non-ptn coding transcript
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What does LAT expression do?
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Facilitates reactication
->doesn't actually have anything to do with latency |
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Describe LAT
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2 kb intron
Spliced from the 1ry LAT transcript |Intron is stable in the nucleus of the latently infected neuron adn persists as a circular lariat form |
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What was the result of probing the fct of LAT in rabbits infected by WT HSV-1 and rabbits infected by HSV virus with dLAT?
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Found extensive apoptosis
-->in 66% of LAT negative infective rabbits --> in 4% of uninfected rabbits or rabbits infected with WT-HSV1 |
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What happens when a plasmid containing LAT was introduced into cells?
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The cells were protected vs several apoptosis inducers
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What does LAT do?
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Prevent killing of latently infected neurons and lets them live longer and maintain reactivation throughout lifetime of organism
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What happens to the frequency of reactivation of the virus over time?
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It decreases
-->With each reactivation, probabyl killing off more and more latently infected neurons |
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What drugs can be used vs herpes?
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Acyclovir
Fanciclocir: modified acyc, with longer T1/2 Valtrex: prodrug with added valine to acyc, stable vs stomach acid. Not active, but metabolized in liver to slowly release the drug |
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What is acycolvir?
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Acycloguanine
Looks like G, but has a cyclic ring at the 5' OH, but lost the 3' OH |
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What happens after acyclovir is taken up?
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It is P and it binds to DNA pol
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What are the 2 effects of acyclovir?
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Chain terminater because has no 3' OH
Binds DNA pol with much higher avidity then G because has no 3' OH |
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Why is it so potent as a drug?
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It is P
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What is the problem with acyclovir?
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Terrible substrate for inital P by host cell kinases
->not P by cell kinases on 1st position |
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How does acyclovir still work?
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But HSV 1/2 both express viral genome that encode thymidine kinases that are very active and can P acyc in 1st position
Then cell kinases take over and all DNA syn in these cells are turned off and those cells dies |
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What kind of a drug is acyc?
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Nucleoside analogue (because cells can only take up nucleosides, not nucleotides)
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Why is acyc good?
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Toxic: therapeutic = 600X therapeutic
No allergies vs this because looks so much like G .: very effective vs actively dividing HSV1/2 |
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Does acyc work vs latent infection?
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No because only have LAT expressed during latency (no thymidine kinase)
.: has no affect on latent virus |
