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Microbiology Exam 2 > HIV and RetroViruses > Flashcards

HIV and RetroViruses Flashcards

1
Q

What is the basic retrovirus structure, including the genes found within its genome?

A
  • RNA genome, positive sense, 2 copies per virion; enveloped
  • gag gene: group specific antigen; polyprotein that is processed by viral protease to make the viral matrix and capsid proteins that surround the genome
  • pol: polyprotein that contains the enzymes reverse transcriptase (RT), integrase, and protease
  • LTR: long terminal repeats; repeated sequences at the end of the genome that help the virus replicate
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2
Q

3 things that makes retroviruses unique and why they are important.

A
  1. They make DNA out of RNA via RT; RT is drug target and it makes mistakes that gives rise to drug resistance
  2. they integrate their DNA into the host chromosome via integrase; integrase is drug target and once integrated, the viral DNA becomes a PERMANENT part of the cell that can only be eradicated by killing the cell which makes HIV a lifelong infection
  3. Protease; important drug target by protease inhibitors
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3
Q

Good and bad of gene therapy with RVs

A

-integrase offers an interesting genetic tool, but inserting genes into the wrong place can lead to tumor formation

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4
Q

Where does HIV integration preferentially occur and why is this bad for gene therapy?

A
  • preferentially integrates at active genes

- bad because it increases its odd of causing cellular transformation

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5
Q

T/F: where integration occurs in gene therapy doesn’t matter.

A
  • False, an attempt to treat SCIDs using RV introduced genes led to insertion in coding region of LMO2 gene and led to leukemia
  • integration conferred longterm protection from the genetic lesion, but where it occurs matters
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6
Q

List the 12 steps of a retrovirus lifecycle and ** which are the steps the viral enzymes act at

A
  1. receptor binding
  2. membrane fusion and entry
  3. uncoating and reverse transcription** RT
  4. nuclear uptake
  5. integration**integrase
  6. transcription
  7. RNA processing
  8. nuclear export
  9. translation
  10. assembly
  11. budding
  12. maturation protease
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7
Q

Name 2 diseases commonly associated with HIV/AIDS

A
  1. Kaposi’s Sarcoma

2. Pneumocystis carinii pneumonia (yeast)

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8
Q

What are 2 ways that depict HIV turning into AIDS?

A
  1. HIV infected persons with CD4+ <200

2. HIV infected and have had an AIDS defining illness, regardless of CD4

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9
Q

What does HAART stand for?

A
  • High Active Antiretroviral Therapy (HAART)
  • has reversed the trend of increasing AIDS deaths
  • *treatment has been expanded to developing countries and as a result, new infections and deaths due to AIDS have finally begun to fall
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10
Q

What does it appear that HIV arose from?

A

-all HIV strains appear to have arisen from a single, common ancestor

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11
Q

When did HIV first infect humans? Where did it come from?

A
  • 1910
  • genetic evidence argues that HIV-1 arose from transmission of SIV from chimpanzees to humans
  • also argues that HIV-2 arose from transmission of SIV from sooty mangabeys to humans
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12
Q

Because HIV was spread to us by other animals, HIV is therefore an example of a _______.

A

-zoonosis

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13
Q

Where within Africa did HIV come from and why was it able to spread to quickly and so soon?

A
  • Southeast village in Cameroon

- Congo river provided a route for the virus to spread

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14
Q

What clades predominate in most parts of the world? Where is the epicenter of the HIV/AIDS pandemic?

A
  • B and C (B mostly in US)

- African is epicenter

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15
Q

Define zoonosis and emerging viruses

A
  • zoonosis: a disease or infection naturally transmitted between vertebrate animals (the reservoir) and humans, may involve insect vectors
  • emerging viruses: often unanticipated zoonoses resulting from changes in environment/human behavior
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16
Q

What does HAART target?

A
  • RT, integrase, protease

- multidrug antivirals used in combination, most often 2 RT and 1 protease inhibitor

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17
Q

Why is HIV considered “a moving target”?

A

-high replication rate coupled with a high error rate in RT means that every base int he viral genome mutates to every other possible base everyday and therefore, monotherapy is likely to fail so combination therapy is needed

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18
Q

What is the spike protein on HIV? What triggers its membrane fusion? What is its receptor?

A
  • EnV
  • triggered by receptor engagement by CD4 AND coreceptor!!! (pH independent so fuses right at membrane)
  • Binds CD4
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19
Q

3 steps to HIV entry

A
  1. Binding to CD4
  2. Binding to coreceptor CCR5 or CXCR4 which is trigger
  3. membrane fusion
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20
Q

What are the co-receptors involved with HIV infection? What type of receptors are they? What are they associated with?

A
  • M-tropic strains use the chemokine R CCR5
  • T-tropic strains use chemokine R CXCR4
  • CCR5 is associated with virus transmission, and can undergo a CoR switch to CXCR4 that is associated (poorly) with disease progression.
  • Many more T cells have CXCR4 so if switch co-receptors, can infect many more cells; associated with faster CD4 declines and progression to AIDS
21
Q

What is the name of the time at which CCR5 switches to CXCR4 called?

A
  • transition point
  • where rate of CD4 decline accelerates
  • *These 2 receptors are now drug targets!
22
Q

WT, ccr5 negative hetero and homozygotes comparison

A
  • WT: get infected normally
  • Heterozygotes: infected normally, progress more slowly
  • Homo: highly resistant to HIV with no signicant side effects except more likely to get West Nile encephalitis
23
Q

Describe in detail how HIV EnV protein causes membrane fusion.

A
  1. trimeric EnV protein binds CD4 which induces conformatioal changes in gp120 that result in exposure of a very highly conserved region in gp120 that is important for coR binding
  2. binding also triggers exposure of fusion peptide that is hydrophobic stretch of AA at N-terminus of gp41 that stabs the cell membrane, becoming an integral component of 2 membranes
  3. for fusion to occur, membranes need to be brought closer together. gp41, in addition to fusion peptide, also have 2 helical regions, of which HR2 likes to bind HR1
24
Q

What does the drug T-20 do and what do it target? Therefore, what type of drug can this be classified as?

A
  • it is a peptide that is based on sequence of HR2
  • it binds HR1 before HR2 can and prevent formation of the 6 helix bundle and blocks fusion as a result
  • membrane fusion inhibitor
25
Q

2 ways to measure HIV infection and asses disease progression

A
  1. Counts of Helper/CD4+ T lymphocytes: measured by flow cytometry with antibodies to CD4, measures immunologic damage by HIV, and used to determine when to treat
  2. Level of HIV RNA in plasma (viral load) measured by PCR assay; used to detect primary infection before antibodies appear, prognosis, therapeutic monitoring
26
Q

What are normal CD4 cell counts? What is the AIDS cutoff? What level is used to determine when to treat?

A
  • 800-1200

- <350 is used to treat

27
Q

3 things PCR assay of viral load is used for

A
  1. diagnosis: HIV RNA detects early viremia of primary infection before antibodies appear
  2. prognosis: predicts CD4 decline, clinical events, and survival
  3. therapeutic monitoring: assesses results of antiretroviral treatment
28
Q

Define the 3 stages of a typical HIV infection

A
  1. Acute phase: immediately upon primary infection, HIV replicates rapidly and is disseminated throughout the body. An abrupt decrease in CD4 T cells in peripheral circulation is seen and causes flu-like symptoms
  2. Clinical latency: immune response to acute phase ensures, with decrease in detectable viremia and some stabiliztion of CD4 T cells followed by progressive loss of CD4 T cells. Most patients remain free of symptoms for several years
  3. AIDS: progressive T cell loss and increased viremia, patient begin to experience signs of clinical progression and develop opportunistic infections which may lead to death
29
Q

Describe symptoms of Acute HIV infection and how diagnosis is made

A
  • acute retroviral syndrome that is often mistake for the flu
  • occurs in about 50% of newly infected people 2-6 weeks after infection and lasts 1-3 weeks
  • symptoms: pharyngitis, fever, adenopathy, skin rash, nausea or vomiting, neurological signs/symptoms
  • bc patients become antibody positive 4-6 weeks after infection, diagnosis in made in this window by viral RNA
30
Q

HIV causes depletion of gut-associated CD4+ T cells and breakdown of mucosal barrier. How does this make them more susceptible to infection?

A

-results in mucosal damage, allowing bacterial products like LPS to enter the blood stream, which in turn activates T cells and makes them more susceptible to HIV infection

31
Q

Define and describe what occurs in the clinical latency period. Name 2 key points of this phase that are important to disease progression and spread.

A

-virus load decreased to new level termed set point (30,000/ml is average)
-patients usually asymptomatic during this period which without tx, lasts 7-10 years
-virus load remains constant, while CD4 levels decline
Key point 1: virus load is best lab marker to predict rate of disease progression
Key point 2: lack of symptoms mean many HIV infections are not detected until the patients presents with AIDS. This delays treatment and helps spread disease

32
Q

Virus load is the best predictor of rate of disease progression. How are the 2 related?

A

-lower virus load set point= less accelerates disease progression

33
Q

4 categories that show the wide variation in the rate/progression to AIDS

A
  1. exposed-uninfecteds: remain HIV- despite virus exposure. ccr5 accounts for only a VERY SMALL number of this group
  2. rapid progressors: some people progress to AIDS quickly within 1-3 years
  3. Long-term nonprogressors: HIV+ for years and not progresses to AIDS (low virus loads)
  4. Elite controllers: subset of longterm nonprogressors who have virus loads below limits of detection (less than 50 copies/ml)
34
Q

List the 5 antiviral categories used to treat HIV and what step of the retrovirus lifecycle that inhibit

A
  1. Fusion inhibitors: block membrane fusion and entry; T20
  2. Coreceptor inhibitors: block receptor binding
  3. RT inhibitors: block uncoating and reverse transcription
  4. Integrase inhibitors: block integration
  5. Protease inhibitors: block maturation
35
Q

Name the 2 kinds of RT inhibitors

A
  1. Nucleoside Reverse transcriptase inhibitors (NRTI): look like nucleotides, RT tries to incorporate them into viral DNA which stops chain elongation
  2. Non-nucleoside RTI (NNRTI): bind to RT as site different from NRTIs. ; allosteric inhibitors
    * because they bind different sites of RT and work by different mechanisms, they are typically used in combination
36
Q

Viruses resistant to NRTIs are sensitive to _________.

A

-NNRTIs and visa-versa

37
Q

Viral gag is a large polyprotein, a portion of which has protease function. Once the virus has formed, what does the protease do? What occurs in presence of protease inhibitor?

A
  • protease clips gag protein generating the matrix, nucleocapsid, and capsid proteins. This is needed for virus to mature and become infectious
  • in presence of PI, virus infects cells normally and new virus particles are produced but these viruses fail to mature and so are noninfectious
38
Q

5 classes of drugs CURRENTLY approved by FDA for HIV therapy

A
  1. NRTI
  2. NNRTI
  3. PIs
  4. Entry inhibitors
  5. Integrase inhibitors
39
Q

What happens when HAART is started?

A
  • virus load constant during clinical latency which means virus production = virus destroyed each day
  • HAART administration causes virus load to fall 2-logs within a day or two; useful for new clinical trials bc if drug doesnt work immediately, it wont work period
40
Q

One of the negative of antiviral therapy is the concept of selective pressure of therapy. Describe what this is, but why it is still somewhat helpful.

A
  • when treatment begins, kill off wild type virus,but some drug-resistant quasispecies remain
  • can be due to inadequate potency, inadequate drug levels, inadequate adherence or pre-existing resistance
  • the resistant species will multiply, but still be at lower levels that before drugs began, and due to acquired mutations, may have less fitness
41
Q

What can happen if patient compliance isn’t met with antiviral therapy?

A
  • when drug levels fall below concentration needed for complete suppression of a given virus species, residual replication allows mutant strains with reduced susceptibility to drug to be produced
  • as mutant grow, replication window widens and viruses with additional mutations are selected that are more resistant
  • ultimately high-level resistance develops toward drug and rebound in viral RNA occurs
42
Q

Give a mechanism for HIV drug resistance

A
  • mutations in RT and protease that confer resistance to antivirals as compensatory mechanisms
  • viral genotypes is highly predictive of phenotype and can lead to better, more individualized medicine regimens
43
Q

If a new patient who is HIV positive comes to you for treatment, what should you do before giving them meds?

A

-draw their blood, genotype their virus and give drugs that work well with their strains/mutations

44
Q

3 ways HIV positive mothers can pass virus to their child; how should you prevent this?

A
  • during pregnancy, during vaginal delivery, and via breast milk
  • screen pregnant women early for HIV and give antivirals during pregnany to reduce transmission to 1% (20-45% without tx)
45
Q

Can HAART eradicate HIV in a patient?

A
  • no, reach undetectable levels but returns if HAART is stopped
  • thought to have viral reservoirs and low level of ongoing replication
46
Q

Give an example of a viral reservoir for HIV

A
  • Memory T lymphocyte

- usually not active so virus just hides out in it

47
Q

What is the bottom line of latent HIV reservoirs?

A
  • guarantees lifetime persistence in the vast majority of patients on current HAART regiments
  • viral reservoir represents an archive of all virus types that have ever circulated in a patient; once a patient fails a drug, resist virus likely resides within patients so you cannot recycle drugs
48
Q

What is the greatest barrier to antivirals and vaccines for HIV?

A
  • the genetic diversity of the virus

- major antigenic drift

49
Q

Due to antigenic drift, HIV stays one step ahead of the ____________.

A
  • humoral response
  • if take antibodies from year 2 of infection and give them to cells from year 1, will kill them, but will not kill present day virus

Microbiology Exam 2 (11 decks)

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