Block 11 - L6-L9 Flashcards
1
Q
Describe the distinctive morphology of restroviral particles on EM.
A
Membrane bilayer, bullet-shaped, electron dense core, hazy extensions of glycoproteins
2
Q
What are the 4 enzymes present in the core of HIV?
A
Reverse transcriptase (RT), RNase H, integrase, protease
3
Q
Describe the RNA contained in the core of HIV.
A
2 single-stranded positive sense RNA
4
Q
What are the two important glycoproteins on the surface of HIV?
A
GP120 (receptor-binding protein) and GP41 (transmembrane protein)
5
Q
What enzymatic activity signifies the presence of retroviruses?
A
RT activity
6
Q
How does HIV enter a cell?
A
One of the three GP41 binds CD4. Structural changes occur in GP120, exposing a binding site, which binds to CCR5 (co-receptor) on the cell.
The virus and cell are brought into close proximity, such that the membrane bilayers coalesce and open a portal for the virus to infect.
7
Q
What is the target immunogen for an HIV vaccine?
A
GP120/GP41
8
Q
What happens to people who do not express the CCR5 co-receptor?
A
They do not get infected by HIV
9
Q
Once the viral core is in the cytoplasm, what happens?
A
Uncoating, reverse transcription, and trafficking of the DNA form into the nucleus.
10
Q
Virion RNA genomes are ___.
A
Diploid
11
Q
What are LTRs seen on the ends of the provirus DNA?
A
Long terminal repeats that promote transcription of the DNA form of the virus
12
Q
Once the viral DNA is in the nucleus of the cell, what are the possible outcomes?
A
- Proviral integration, but no transcription - latent infection
- Proviral integration into germ line cells - endogenous (vertical) transmission
- Proviral integration into an essential cellular gene - cell may die
- Proviral integration near a cellular oncogene - cell may transform and cancer may develop
- Proviral integration followed by DNA transcription - production of progeny viruses
13
Q
What happens after integration?
A
Transcription, nuclear export, translation, assembly, budding, and maturation
14
Q
What happens in maturation of HIV?
A
Immature HIV condenses gag proteins into a conical shape; done via a viral protease
15
Q
Current HIV-1 is related to what original virus?
A
HIV-cpz, a chimpanzee lentivirus
16
Q
How is HIV transmitted?
A
Plasma, semen, vagina/cervical fluid, breast milk
NOT saliva, sweat, tears, bronchial fluid, urine feces
HIV is not a particularly infectious virus and is not contagious like measles (can be reduced/killed by air drying, heating, bleach, alcohol, pH extremes, detergents)
Not spread by respiratory, alimentary, or vector routes
17
Q
HIV has evolved into what two groups? One of these groups has evolved into ___.
A
Groups - M (main) and O (outlier)
M group has evolved into clades
18
Q
Which clade predominates in the US and Europe? In Thailand?
A
US/Europe - B
Thailand - E
19
Q
Evolution of variability of HIV is largely in ___.
A
Surface glycoproteins GP120 and 41
20
Q
Evolution and variability in HIV GP120 determines virus tropism for which cells?
A
Macrophages and CD4+ T cells
21
Q
Discuss the pathology of HIV infection?
A
Robust, cytotoxic infection causing death of CD4+ T cells and syncytia formation in lymph nodes
22
Q
What are the 3 stages of HIV-induced disease?
A
- Acute (4-8 weeks)
- Latent (up to 12 years)
- AIDS (2-3 years)
23
Q
Describe the infection of CD4+ T cells over the course of these stages.
A
Infection occurs and a large drop in T-cells occurs during the acute phase; this rebounds somewhat (not to pre-infection levels), and decreases slowly over the latent period. It drops completely in AIDS, leading to death
24
Q
Describe the Ab over the course of the stages of HIV.
A
The acute phase has a peak and drop in viremia, which then remains fairly low during the latent period. It increases without stopping in AIDS.
Antibodies to HIV-specific CTL appear first, followed by Ab to the HIV envelope and to p24. These stay high during the latent period and drop in AIDS.
25
What are the symptoms of acute infection with HIV?
Monolike syndrome (fever, fatigue, swollen lymph nodes), observed ~3 weeks after initial infection
26
What are the symptoms of clinical latency and what does this mean for the virologic latency?
Few if any clinical manifestations, typically lasts 8-12 years
NOT virologic latency - continued, high levels of viral replication, easily detectable in blood of patients
27
When CD4+ T cell counts fall below 350 cells/microliter, what AIDS-related symptoms appear?
Oral lesions
Basal cell carcinomas
Activation of latent herpes
Mycobacteria infections
28
When CD4+ T cell counts fall below 200 cells/microliter, what more severe AIDS-related symptoms appear?
Protozoal, bacterial, and fungal infections (pneumonia with Pneumocystis carnii, CMV retinitis, oral leukoplakia due to candida)
Viral infections and malignancies (Kaposi sarcoma due to HSV8)
Neurological disorders (AIDS dementia)
29
What is the goal of HAART (Highly active antiretroviral therapy)?
Lower the virologic set point, which slows disease progression
30
What is the indication to start HAART?
Definitive laboratory evidence of HIV
31
What types of drugs are used in HAART?
RT inhibitors (block reverse transcriptase) and protease inhibitors (prevent virion capsid morphogenesis), used concomitantly
32
What are the AE of long-term HAART?
Heart disease, diabetes, liver disease, certain cancer, anemia
Clinical AE - diarrhea, N/V, weakness, lipodystrophy
33
Why must HAART be prolonged?
Drug-resistant viruses are easily formed, as HIV is mutable
HIV provirus can stay in latently-infected cells for a long time
34
Compare HTLV (lymphotropic retrovirus) with HIV lentivirus.
Similar patterns of transmission, both are common
HTLV has lower disease penetrance than HIV
HTLV clinical latency period is longer than HIV (20+ years from infection to clinical disease)
HTLV causes T cell leukemia, which HIV causes T cell death and immunosuppression
35
How does HTLV cause T cell leukemia?
Encodes tax, an accessory protein which induces cell proliferation
36
Which cell type is most important for disseminating HIV into the central nervous system?
Macrophages
37
What is the genome and family of HIV?
Positive strand RNA lentivirus
38
What method for detection of HIV infection is the most rapid and now widely used?
RT-PCR for detection of viral genetic information
39
What is the current method of detection of HIV?
Serology and confirmation by Western blot
40
What is the mechanism of pathogenesis of HIV?
HIV targets CD4+ T cells and macrophages, causing a flu-like syndrome
Chronic viral replication results in a depletion of CD4+ T cells during a period of clinical latency
Low T cell count results in susceptibility to opportunistic infections and clinical AIDS
41
Are there any available anti-virals to treat patients with HIV?
Yes, triple drug therapy is required to prevent drug resistant mutants from arising during treatment. Antivirals are a combination of reverse-transcriptase inhibitors, protease inhibitors and integrase inhibitors
42
Is there a vaccine available against HIV?
No
43
Are there long-term consequences to HIV infection?
Progression to Acquired Immunodeficiency Syndrome (AIDS)
44
List the major viruses that can cause CNS disease.
1. Herpes
2. Enterovirus
3. Arbovirus
4. Measles
5. Rabies
6. Prions
7. HIV
45
Of the 7 major viruses that can cause CNS disease, which are present in a specific geographic location?
Arbovirus (tropics)
46
Of the 7 major viruses that can cause CNS disease, which are predominantly found in children?
Enterovirus and measles
47
Of the 7 major viruses that can cause CNS disease, which are predominantly found in the elderly?
Arbovirus
48
Of the 7 major viruses that can cause CNS disease, which are predominantly found in adults?
HIV
49
Of the 7 major viruses that can cause CNS disease, which present in the summer?
Enterovirus and arbovirus
50
What are the steps required for neuronal virus infection?
1. Enter the neuron at the axon, sensory terminal, or cell body, depending on the site of infection
2. Transport the virus particle or subviral particle to the neuronal cell body where the virus replication occurs
3. Replicate the virus genome
4. Assemble virus particles that egress from the infected neuron in a directional manner
51
What are the manifestations of HSV infection?
Primary oropharyngeal herpes and recurrent labialis
Genital herpes - primary and recurrent
Also - encephalitis, keratitis, mucocutaneous disease (immunocompromised), neonatal herpes
52
How does herpes infect the CNS (rare)?
Via olfactory neurons (dendrites are exposed in the olfactory epithelia)
53
What is unique about the neuronal transport of herpes viruses?
Bidirectional
54
How is herpes encephalitis diagnosed?
PCR of CSF
55
What is the most common cause of sporadic viral encephalitis?
HSV
56
What are the neurological sequelae of enterovirus infection?
Meningitis (primarily), sometimes SC involvement, leading to myelitis and paralysis
57
What are two common arbovirus (flavivirus) infections?
West Nile Virus and Dengue fever
58
How are flavivirus infections transmitted?
Skin inoculation by an insect; infect dendritic cells of the skin -> lymph node -> viremia and CNS infection
59
Describe the transmission cycle of West Nile Virus.
Endemic in insects and birds, enters humans (but not transmitted to other humans)
60
What does WNV cause?
Meningitis
61
___ is associated with microcephaly in infants.
Zika virus
62
What is the rare CNS sequelae of measles infection?
SSPE - develops many years after acute disease
63
Describe the rabies virus particle structure.
Bullet shaped, RNA in the center, lipid envelope, trimeric G glycoprotein trees (bind rabies to neurons)
64
How is rabies transmitted?
Enters tissue from saliva of a biting animal, replicates in muscle near the bite, moves up the PNS to the CNS via the spinal cord (binds to ACh receptors), reaches brain (fatal encephalitis) and salivary glands (can be transmitted)
Uni-directional retrograde transport; fast axonal transport
65
What is the incubation period of rabies infection?
20-90 days
66
How can rabies be treated prophylactically?
Eliminate the virus prior to invasion of the neurons (wash wound, IgG)
67
What are 4 infectious encephalopathies in humans?
Kuru, CJD, GSS disease, FFI
68
How do prions differ from viruses?
No nucleic acid, no defined morphology, no disinfection, no cytopathologic effect, no immune response, no interferon production, no inflammatory response
69
What is seen in the brain in kuru?
Plaques
70
How are prion plaques formed?
Formation of a catalyst (altered form of an endogenous protein), altered proteins form aggregates and accumulate in neurons
71
What is a common prion protein?
Phosphatidylinositol glycan
72
What is the most common cause of epidemic encephalitis in the USA?
WNV
73
How is West Nile virus usually transmitted?
Mosquito vector with marsh bird reservoir
74
How is West Nile Virus typically diagnosed?
RT-PCR and serology
75
What is the pathogenesis of West Nile Virus?
Viremia leading to infection of the CNS
76
Are there any effective therapies against West Nile Virus?
No
77
Is there a vaccine currently available for West Nile virus?
No
78
What population is most likely to exhibit severe disease after West Nile virus infections?
Adults over 60 y/o
79
What are the 8 human herpesviruses?
```
HSV1
HSV2
VZV
EBV
CMV
HHV6
HHV7
HHV8
```
80
What is caused by acute infection and reactivation of HSV1?
Acute - cold sores
| Reactivation - cold sores
81
What is caused by acute infection and reactivation of HSV2?
Acute - genital herpes
| Reactivation - genital herpes
82
What is caused by acute infection and reactivation of VZV?
Acute - chicken pox
| Reactivation - shingles
83
What is caused by acute infection and reactivation of EBV?
Acute - infectious mononucleosis
| Reactivation - lymphoma/cancer
84
What is caused by acute infection and reactivation of CMV?
Acute - broad spectrum
| Reactivation - pneumonia
85
What is caused by acute infection and reactivation of HHV6 and HHV7?
Acute - roseola
| No evidence of reactivation
86
What is caused by acute infection and reactivation of HSV8?
No evidence of acute infection
| Reactivation - Kaposi's sarcoma
87
What is the general structure of herpesvirus?
dsDNA, enveloped virus
Lots of glycoproteins (gB-gN)
Tegument (proteins in the layer between the envelope and capsid)
Capsid with DNA
88
Describe the sequence of transcription events in herpesvirus infection.
Immediate (peaks and declines in 3 hours)
Early (peaks and declines in 8 hours) - DNA synthesis proteins
Late (peaks beginning at 4 hours, stays elevated) - virion proteins
DNA production (begins at 3 hours, stays elevated)
89
Where is the viral capsid assembled in a cell infected with herpesvirus?
In the nucleus
90
What is the primary infection caused by HSV type 1?
Usually cold sores, sore throat, fever, and rarely, encephalitis; less frequently found as a genital infection
91
Describe the infection and pathogenesis of HSV type 1.
Primary lytic infection of epithelial cells
Virus infects sensory neurons (latency-associated transcripts - LATs - are the only vmRNA present)
Reactivation - virus travels back to epithelial cells and causes lesions and shedding
92
Latent infection with HSV1 is asymptomatic and no virus is produced. Where does the viral DNA reside?
Sensory cells of the trigeminal nerve ganglion
93
What is the primary infection caused by HSV type 2?
Vesicular eruptions on the genitalia spread by sexual contact; affects both sexes, less frequently found as herpes labialis (cold sores)
94
Where does latent HSV2 reside?
Sensory cells of the sacral ganglion
95
What can be used to treat HSV?
Acyclovir
96
What is the MOA of acyclovir?
Viral thymidine kinase converts acyclovir to acycloGMP; cellular kinases convert this to acycloGTP, which is a chain terminator when incorporated into DNA
97
What causes resistance to acyclovir?
Mutations in the gene encoding the viral thymidine kinase (needed to activate the drug) and/or the viral polymerase (no longer efficiently binds the drug)
98
What is the MOA of pritelivir?
Inhibits the herpesvirus helicase-primase
99
Describe the primary infection with varicella zoster.
Infection occurs in seasonal epidemics as chicken pox, contracted from another infected individual, results in generalized vesicular rash
100
What are the clinical features of VZV infection?
Mild prodrome (fever, malaise) for 1-2 days
Successive crops of pruritic vesicles (2-4 days) - vesicles will be in all stages
Appear first on head, most concentrated on trunk
Generally mild in healthy children
101
What are complications of VZV infection?
Bacterial infection of lesions, CNS manifestations, pneumonia, hospitalization, death
102
What is the peak incidence of VZV?
4-9 y/o
103
Who dies most often from VZV in healthy people?
<1 y/o, >30 y/o
104
Describe the Varicella vaccine.
Live-attenuated virus, 95% effective, probably long-lasting, 1 dose + booster, administered with MMRV
105
Where is VZV latent?
Cells of the dorsal root ganglia
106
How does reactivated VZV present?
Shingles - unilateral painful vesicular eruptions localized to a dermatome, usually in the head or upper trunk
107
What provides passive immunity to VZV?
VZIG
108
What is the most common primary manifestation of HSV1?
Cold sores
109
How is HSV1 usually transmitted?
Close contact such as kissing, wrestling or sex
110
How is HSV1 typically diagnosed?
Clinical presentation
111
What is the pathogenesis of HSV1?
Primary lytic infection of epithelial cells followed by infection of sensory neurons of the trigeminal ganglia where the virus can become latent, and reactivation can occur.
112
Are there any anti-virals available against HSV1?
Acyclovir and Pritelivir
113
Is there a vaccine available for HSV1?
No
114
Are there any possible consequences of HSV1?
Latent infection with the possibility for recurrence
115
What is the most common primary manifestation of HSV2?
Vesicular eruptions on the genitalia
116
How is HSV2 usually transmitted?
Close contact such as kissing, wrestling, or sex
Mother to newborn
117
How is HSV2 diagnosed?
PCR of viral DNA from the lesion
118
What is the pathogenesis of HSV2?
Primary lytic infection of epithelium of genitalia followed by latent infection of sensory cells of the sacral ganglion. Recurrent infection can occur, usually at the same sight as the primary infection.
119
Are there any anti-virals available against HSV2?
Acyclovir and Pritelivir
120
Is there a vaccine available for HSV2?
No
121
Are there any consequences of HSV2 infection?
Latent infection/recurrence
Neonatal infections leading to recovery, neurological impairment, or death
122
What is the most common primary manifestation of Varicella-zoster infection?
Chicken pox
123
How is Varicella-zoster usually transmitted?
Respiratory
124
How is infection with Varicella-zoster typically diagnosed?
Clinical presentation
125
What is the pathogenesis of Varicella-zoster infection?
Primary systemic infection with generalized, vesicular rash that results in latent infection that can reactivate as shingles.
126
Are there any anti-virals available to treat Varicella-zoster infection?
Acyclovir
127
Is there a vaccine available for Varicella-zoster?
Live-attenuated vaccine
128
Are there any possible consequences of Varicella-zoster?
Latent infection with the possibility for recurrence as shingles
129
What is caused by primary infection with EBV?
Asymptomatic infection
| Infectious mononucleosis
130
Discuss the epidemiology of EBV infection.
Causes lifelong infection, asymptomatic shedding of virus
Transmitted via saliva
Teens and adults at highest risk for infectious mononucleosis
Worldwide distribution, no seasonal incidence
131
What is the disease mechanism of EBV?
Virus in saliva infects epithelia and spreads to B cells. Infection promotes growth of B cells. T cells kill/control B-cell outgrowth, promoting latency in B cells. Severe disease occurs in T-cell deficient patients
132
What is seen on blood smear in EBV?
Atypical lymphocytes (Downey cells)
133
How is EBV infection detected?
```
Monospot test (detects heterophile Ab)
Ab to EBV VCA (viral capsid Ag)
```
134
In addition to infectious mono, what clinical syndromes can be caused by EBV?
Post-transplant lymphoproliferative disorder (PTLD)
Hairy oral leukoplakia (w/AIDS)
African Burkitt's Lymphoma (w/malaria as a co-factor)
Nasopharyngeal carcinoma (China)
135
What does primary infection with CMV cause?
Asymptomatic infection
Mononucleosis
Fetal/neonatal infection (cytomegalic inclusion disease)
136
What does persistent infection/carrier state with CMV cause?
Asymptomatic shedding, serious complications in immunocompromised patients (multisite symptomatic disease)
137
How can you distinguish between mono caused by CMV or EBV?
CMV - negative heterophile Ab
| EBV - positive heterophile Ab
138
How is CMV transmitted?
Blood, secretions (breast milk and semen are included)
139
Discuss the pathogenesis of CMV.
Acquired from blood/secretions, causes productive infection of epithelium, establishes latency in T-cells, macrophages, and other cells; suppression of CMI allows recurrence
140
How is CMV infection diagnosed?
PCR (detect CMV DNA), serology (CMV IgM and IgG), cytology/histology (owl eye inclusion body)
141
How is CMV treated?
Ganciclovir (activated in CMV-infected cells)
Letermovir (prophylaxis in hematopoietic-cell transplant)
142
What is the major AE of ganciclovir?
Bone marrow toxicity
143
What is the MOA of letermovir?
Targets CMV terminase complex (normally allows for packaging of DNA into capsid)
144
What are the symptoms of HHV-6 and 7 infection?
Roseola - incubation 4-7days) rapid onset of high fever (103-105 degrees F for 2-4 days), generalized rash 24-48 hours later + no fever, T-cells resolve the infection
145
Where is HHV6 and 7 latent?
T cells
146
How is roseola diagnosed and treated?
No rapid diagnostic currently available, no specific therapy
147
What is the most common neoplasm in patients with AIDS?
Kaposi's sarcoma
148
What is seen on H&E in Kaposi's sarcoma?
Spindle-shaped tumor cells, neovascularization, inflammatory infiltrate
149
What causes Kaposi's sarcoma in patients with AIDS?
HHV-8 - transmitted sexually, resolved by T-cells, reactivated during immunosuppression
150
What is the most common primary manifestation of infection with CMV?
Aysymptomatic
Severe disease in neonates
Infectious mono (~10% of cases in young children)
151
How is CMV most commonly transmitted?
Saliva, secretions and mother to newborn
152
How can infection with CMV be diagnosed?
PCR of viral DNA from newborn patient sample, serology for CMV specific Ab from patients with infectious mono, owl eye inclusion bodies on histology in CMV pneumonia
153
What is the pathogenesis of CMV?
Virus infects epithelium and establishes latency in T cells, macrophages, and other cell types. Virus shedding from saliva and secretions occurs sporadically throughout life
154
Are there any anti-virals available to treat infection with CMV?
Ganciclovir
155
Is there a vaccine available against CMV?
No
156
Are there any possible consequences of CMV infection?
Life-long sporadic shedding of virus
157
What is the most common clinical primary manifestation of infection with EBV?
Infectious mononucleosis
158
How is EBV most commonly transmitted?
Contact with saliva
159
How can infection with EBV be diagnosed?
Monospot test for heterophile Ab and/or serology for Ab against VCA
160
What is the pathogenesis of EBV?
Virus infects epithelia spreading to B cells where it replicates. Virus becomes latent in B cells with sporadic recurrence
161
Are there any anti-virals available to treat infection with EBV?
No
162
Is there a vaccine available against EBV?
No
163
Are there any possible long term consequences of EBV infection?
```
Burkitts lymphoma (malaria co-factor)
Nasopharyngeal carcinoma (Chinese herb co-factor)
latent infection with sporadic virus reactivation and shedding
```
164
What is the most common clinical presentation of Roseola?
Sudden onset of fever for 2 days, followed by rash in infants
165
What infectious agent causes Roseola?
HHV6 and 7
166
How is Roseola most commonly transmitted?
Respiratory
167
How can infection with Roseola be diagnosed?
Clinical presentation
168
What is the pathogenesis of Roseola?
Virus incubation for 4 to 7 days, followed by high fever. When the fever ends a rash will appear. Latency is established in T cells with no known reactivation
169
Are there any anti-virals available to treat infection with Roseola?
No
170
Is there a vaccine available against Roseola?
No
171
Are there any possible consequences of Roseola infection?
Latent infection with no known clinical recurrence
172
In what subset of patients would you normally see Kaposi's sarcoma?
Patients with HIV/AIDS
173
How is HHV-8 most commonly transmitted?
Sexual contact
174
How can infection with HHV-8 be diagnosed?
Clinical presentation and PCR for viral DNA
175
What is the pathogenesis of HHV-8?
T cells control and resolve infection, but activation of Kaposi's lesions occurs during immunosuppression
176
Are there any anti-virals available to treat infection with HHV-8?
No, but treating patients with AIDs with HAART will restore T cells that will control the HHV-8 infection.
177
Is there a vaccine available against HHV-8?
No
178
Are there any possible consequences of HHV-8 infection?
Kaposi's sarcoma in immunocompromise
