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Hematology > HIV > Flashcards

HIV Flashcards

1
Q

Describe the basic structure of HIV.

A
  • The viral particle buds out and retains host membrane so surface of virus has both host and viral proteins
  • about 30 gp120 trimers on surface of each indic particle -essential in attachment to host cell
  • Inside core are 2 ssRNA and a reverse transcriptase
  • particle surrounded by glycan shield-makes it difficult for antibodies to get through and achieve effective immune response
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2
Q

Describe the basics of HIV genes.

A

LTR: long terminal repeats that act like promoter
Gag, Pol, env: code for structural proteins of virus and enzymes required for replication
vif, vpr, tat, rev, vpu, nef: encode proteins that regulate viral life cycle and contribute to host cell injury

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3
Q

Why do the HIV particles in infected indivs vary so much from person to person?

A

-High mutation rate (106 > TCR genes) partly because doesn’t have nucleic acid repair mechanism
-Marked genomic variability
-Selective target cell tropism
MØ’s (CD4 & CCR5)
T-cells (CD4 & CXCR4)
T-cells (CD4 & CXCR4 or CCR5)
-In vivo virulence variability

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4
Q

Briefly, what is the life cycle of HIV?

A
  1. attachment to host cell via CD4 +coreceptor and fusion of HIV to the host cell surface
  2. HIV RNA, reverse transcriptase, integrase, and other viral proteins enter host cell
  3. viral DNA is formed from ssRNA by reverse transcriptase
  4. viral DNA is transported across the nucleus and integrated into host DNA by integrate
  5. new viral RNA used as genomic RNA to make viral proteins
  6. new viral RNA and proteins move to cell surface and new, immature HIV forms
  7. The virus matures via protease releasing individual HIV proteins
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5
Q

What are ways in which HIV spreads in the body?

A
  1. Release of cell free virus
  2. exosome-mediated transmission
    - more infectious than free virus
  3. cell to cell transfer:
    - more rapid and efficient
    - allows evasion of host defenses, no way for antibody to get into synapse
    - permits transmission despite ARV Rx
    - uninfected dendritic cells present HIV to T cells, an actin dependent synapse forms between them
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6
Q

What happens in the acute phase of HIV infection?

A
  • in 2 weeks, 50% of all memory (CCR5-) CD4+ T cells are gone
  • most cells mucosa associated
  • most of the cells infected and killed are not activated, small pieces of DNA that virus makes are recognized by nucleic acid sensors in cytoplasm that induce cell suicide
  • immune cytotoxicity and Fas-FasL mediated apoptosis may contribute
  • CCR5+ CD45RA- CD4+ T-cells (activated, memory TH1 effectors) are the 1° lytic targets of HIV
  • CD4+ T-cell in blood are primarily CCR5-
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7
Q

What happens in the chronic phase of HIV infection?

A
  • a lot of virus particles produced and eliminated daily
  • a lot of CD4+ T cells eliminated and mostly replaced daily
  • activated CD4+ T cells are the primary source of and target for free virus
  • with a single drug treatment, virus becomes drug resistant after 2 weeks
  • obstacle to treatment: resting CD4+ central memory T cells have T1/2 for months and are reservoirs for the virus. can take decades of treatment to eliminate
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8
Q

How does HIV evade the host immune response?

A

-low gp120 spike density on virion surface
-conformational shielding of critical epitopes, critical components of gp120 folded into the inside of protein
-envelop heterogeneity and glycosylation: higher glycan density promotes viral ability to evade antibodies
-preferential infection of HIV specific T cells: loss of CD4+ HIV specific response
-role of HIV regulatory gene products, e.g.:
Vpr: suppresses Il12 production from macrophages
Vif: inhibits APOBEC3 which edits retroviral cDNA and induces fatal mutations
Nef: decresases CD4 expression, blocks apoptosis
Vpu: inhibits tethering (prevents HIV release from cell) and NKT cell activation
-emergence of escape mutants that overcome host capacity to generate cytotoxic lymphocytes
-virion expression of host complement regulatory proteins
-TREX1 inhibits innate immune response to reversely transcribed HIV DNA
-chronic infection exhausts effector T cells
-Macrophages and T cells “archive” virus

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9
Q

How does HIV induce immune deficiency?

A

-Rapid, early destruction of ~50% mucosal memory T-cells
-CD4+ T-cell depletion: mechanistic examples:
Direct cytotoxicity – activation of DNA- dependent protein kinase during integration
Syncytia formation: fusion of infected cell and uninfected cell to b/c nonfunctional giant cell
-Decreased BM production of lymphoid precursors
-Decreased thymic output of “new” T-cells
-Later destruction of lymph node architecture–> impaired clonal expansion

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9
Q

How does HIV induce immune deficiency?

A

-Rapid, early destruction of ~50% mucosal memory T-cells
-CD4+ T-cell depletion: mechanistic examples:
Direct cytotoxicity – activation of DNA- dependent protein kinase during integration
Syncytia formation: fusion of infected cell and uninfected cell to b/c nonfunctional giant cell
-Decreased BM production of lymphoid precursors
-Decreased thymic output of “new” T-cells
-Later destruction of lymph node architecture–> impaired clonal expansion

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10
Q

Outline the pathogenesis of HIV.

A
  1. primary infection of cells in blood, mucosa
  2. Infection established in lymphoid tissues
  3. Acute HIV syndrome, spread of infection throughout body
  4. Immune response to virus
  5. Clinical latency: establishment of chronic infection, furs trapped in lymphoid tissues by follicular DCs, low level virus production
  6. Other microbial infections/cytokines–>increased viral replication
  7. AIDS: destruction of lymphoid tissue, depletion of CD4+ T cells
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10
Q

Outline the pathogenesis of HIV.

A
  1. primary infection of cells in blood, mucosa
  2. Infection established in lymphoid tissues
  3. Acute HIV syndrome, spread of infection throughout body
  4. Immune response to virus
  5. Clinical latency: establishment of chronic infection, furs trapped in lymphoid tissues by follicular DCs, low level virus production
  6. Other microbial infections/cytokines–>increased viral replication
  7. AIDS: destruction of lymphoid tissue, depletion of CD4+ T cells
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11
Q

What is the pathophysiology of HIV?

A
  1. T cell deficiency/dysfunction–>opportunistic infections
  2. CNS microglial infection–>neuroencephalopathy
  3. inappropriate/uncontrolled immune activation–>proliferative disorders and systemic cytokine effects (chronic sickness)
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11
Q

What is the pathophysiology of HIV?

A
  1. T cell deficiency/dysfunction–>opportunistic infections
  2. CNS microglial infection–>neuroencephalopathy
  3. inappropriate/uncontrolled immune activation–>proliferative disorders and systemic cytokine effects (chronic sickness)
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12
Q

What are the current epidemiological trends of HIV?

A
  • The percentage of AIDS diagnoses among whites has decreased while the percentages among blacks/African Americans and Hispanics/Latinos have increased.
  • blacks and latinos disproportionally affected compared to their population in US
  • most diagnoses of HIV in males due to MSM contact
  • most diagnoses of HIV in females due to heterosexual contact
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12
Q

What are the current epidemiological trends of HIV?

A
  • The percentage of AIDS diagnoses among whites has decreased while the percentages among blacks/African Americans and Hispanics/Latinos have increased.
  • blacks and latinos disproportionally affected compared to their population in US
  • most diagnoses of HIV in males due to MSM contact
  • most diagnoses of HIV in females due to heterosexual contact
13
Q

What are the HIV screening recommendations put out by the CDC?

A

-Routine for all persons ages 13-64
-Additionally test all patients:
Tested or treated for an STD
Initiating TB tx
Pregnant women
Women with undocumented HIV status at L&D
-Repeat screening annually for high risk
-Opt-out

13
Q

What are the HIV screening recommendations put out by the CDC?

A

-Routine for all persons ages 13-64
-Additionally test all patients:
Tested or treated for an STD
Initiating TB tx
Pregnant women
Women with undocumented HIV status at L&D
-Repeat screening annually for high risk
-Opt-out

14
Q

What are the diagnostic tests for HIV?

A
  1. Standard HIV antibody tests
    ELISA:tests the antibody to all HIV proteins
    Western Blot: measures antibodies to 8 main HIV gene (2/8 must be positive)
  2. OraQuick Advance Rapid HIV 1/2 test
    -takes 30 mins versus
  3. HIV generation 4: Antigen/Antibody Test
  4. CD4+ count: surrogate marker of immune function
    -strongest predictor of disease progression, prognosis
  5. Viral load: quantitative measurement of virus in blood (copies/ml)
    -surrogate marker for treatment response
  • At time-zero of exposure – all tests will be negative (unless prior exposure).
  • By week 1-4 the acute infection viremia will be detectable by viral load
  • By week 4-6 or so the antibodies will start to be detectable: EIA ab +/- WB ab -
  • around month 3 or so the WB will finally have the requisite minimum 3 antibodies for the antibody test result to be called HIV positive.
  • initially detectable only by viral load for acute infection
  • chronic infection: screen with ELISA and confirm with western blot
14
Q

What are the diagnostic tests for HIV?

A
  1. Standard HIV antibody tests
    ELISA:tests the antibody to all HIV proteins
    Western Blot: measures antibodies to 8 main HIV gene (2/8 must be positive)
  2. OraQuick Advance Rapid HIV 1/2 test
    -takes 30 mins versus
  3. HIV generation 4: Antigen/Antibody Test
  4. CD4+ count: surrogate marker of immune function
    -strongest predictor of disease progression, prognosis
  5. Viral load: quantitative measurement of virus in blood (copies/ml)
    -surrogate marker for treatment response
  • At time-zero of exposure – all tests will be negative (unless prior exposure).
  • By week 1-4 the acute infection viremia will be detectable by viral load
  • By week 4-6 or so the antibodies will start to be detectable: EIA ab +/- WB ab -
  • around month 3 or so the WB will finally have the requisite minimum 3 antibodies for the antibody test result to be called HIV positive.
  • initially detectable only by viral load for acute infection
  • chronic infection: screen with ELISA and confirm with western blot
15
Q

What are the acute clinical manifestations of HIV infection?

A

-fever
-lymphadenopathy
-pharyngitis
-rash
-myalgia or arthralgia
-diarrhea
-headache
-nausea and vomiting
Onset <6 weeks, duration 2-8 weeks

15
Q

What are the benefits and risks of starting early ART therapy?

A

-Benefits:
Control of viral replication easier to achieve/maintain
Delay or prevention of immunodeficiency
Lower risk of resistance
Decreased risk of HIV transmission
Reduced risk of non-AIDS diseases (cancer, CHD)
-Risks:
Drug-related reduction in quality of life
Cumulative drug-related adverse events
Development of drug resistance in those with poor adherence
Limitation of future treatment options
Increased risky behavior

16
Q

What are the chronic manifestations of symptomatic HIV?

A 
Wasting
Thrush
Fever for greater than two weeks
Diarrhea for greater than 1 month
ITP
Oral Hairy Leukoplakia
Herpes Zoster
-In women, additionally can have:
Recurrent Vulvovaginal Candidiasis
Cervical Dysplasia
Carcinoma in situ of the cervix
Pelvic Inflamatory Disease (P.I.D)
-Associated with chronic HIV
Onychomycosis of the fingernails
Seborrheic Dermatitis
Persistant or severe fungal infections of the skin
Syphillis, neurosyphillis, or other STI’s
16
Q

What are important Protease inhibitors (PIs) drugs? What are their side effects?

A
  • Atazanavir (ATV)/ritonavir (low dose): yellow eyes due to increase indirect bilirubin, PR prolongation. Ritonavir is used to boost drug by suppressing CYP 3A4 metabolism
  • Darunavir (DRV)/ritonavir (low dose): Rash

PIs have higher genetic barrier to resistance

17
Q

How is AIDS defined?

A

CD4 < 200
CD4 < 14%
AIDS defining conditions: e.g. Karposi’s, candiadiasis, herpes simplex, TB, pneumonia, PCP, etc.

17
Q

How is AIDS defined?

A

CD4 < 200
CD4 < 14%
AIDS defining conditions: e.g. Karposi’s, candiadiasis, herpes simplex, TB, pneumonia, PCP, etc.

18
Q

What is the natural history of HIV disease?

A
  • lab evidence of infection: asymptomatic
  • lab evidence of immunosuppression: asymptomatic
  • symptomatic HIV disease
  • opportunistic disease AIDS
  • death
18
Q

What is the natural history of HIV disease?

A
  • lab evidence of infection: asymptomatic
  • lab evidence of immunosuppression: asymptomatic
  • symptomatic HIV disease
  • opportunistic disease AIDS
  • death
19
Q

Where in the life cycle of HIV are the targets of HIV drugs?

A
  1. co-receptor antagonists: prevent virus attachement
  2. Fusion inhibitors: prevent virus entry
  3. Nucleoside and nonnucleoside RT inhibitors: inhibit reverse transcriptase
  4. Integrase inhibitors
  5. Protease inhibitors: prevents HIV activation
20
Q

Who do we start on ART?

A

Everyone with AIDS or CD4 500: Also recommended, but supported only observational studies
Recommendation driven in part by reductions in non-AIDS mortality and particularly as a means to reduce HIV transmission
Consider holding if there is a very low HIV RNA

21
Q

How is the timing of ART initiation affected with opportunistic infections and malignancies?

A

-Tuberculosis
Within 2 weeks if CD4 50
-PCP: As soon as patient is stable
-CNS infections
Due to risk of immune reconstitution inflammatory syndrome (IRIS), delay ART until major improvement
-Lymphoma and Kaposi sarcoma
Will respond better to chemo if ART is initiated

22
Q

What are the benefits and risks of starting early ART therapy?

A

-Benefits:
Control of viral replication easier to achieve/maintain
Delay or prevention of immunodeficiency
Lower risk of resistance
Decreased risk of HIV transmission
Reduced risk of non-AIDS diseases (cancer, CHD)
-Risks:
Drug-related reduction in quality of life
Cumulative drug-related adverse events
Development of drug resistance in those with poor adherence
Limitation of future treatment options
Increased risky behavior

23
Q

What is the mechanism of nucleoside reverse transcriptase inhibitors (NRTIs)? What are examples of NRTIs and their side effects?-

A

-mechanism:
Nucleoside analogs
Must undergo phosphorylation intracellularly to active form
Compete with natural nucleosides for incorporation into growing DNA chain
Act as chain terminators after incorporation
Most are renal eliminated
-Emtricitabine (FTC): no major issues
-Tenofovir (TDF): rare fanconi syndrome, greater loss of bone mineral density/fracture
-Abacavir (ABC): hypersensitivity potentially fatal
-Lamivudine (3TC): No major issues
Most patients take TDF and FTC

24
Q

What are important Protease inhibitors (PIs) drugs? What are their side effects?

A
  • Atazanavir (ATV)/ritonavir (low dose): yellow eyes due to increase indirect bilirubin, PR prolongation. Ritonavir is used to boost drug by suppressing CYP 3A4 metabolism
  • Darunavir (DRV)/ritonavir (low dose): Rash

PIs have higher genetic barrier to resistance

25
Q

What are the important non-nucleoside reverse transcriptase inhibitors (NNRTIs)? What are their side effects?

A
  • Efavirenz (EFV): CNS problems like dizziness, confusion, dreams, hallucination, rash, hypersensitivity, possible teratogenicity
  • can feel like bad hangover with cloudy thinking and difficulty on the job

-EFV sold in combo pill with FTC-TDF NRTIs, so patients like it despite CNS problems

26
Q

What are important integrase inhibitors? What are their side effects?

A
  • Raltegravir (RAL): headache, nausea, diarrhea, but no severe side effects
  • Elvitegravir (ELV): must be boosted. GI effects with single dose with cobisistat/TDF/FTC.
  • Dolutegravir (DTG): single dose, no boosting. less potential for drug resistance

-RAL and ELV: only single viral mutation needed to have resistance against them.

37
Q

What are the 2013 DHHS antiretroviral guidelines?

A
  • 2 nucleoside RT inhibitors (tenofovir+emtricitabine FTC+TDF) PLUS one of the following:
  • a protease inhibitor: Atazanavir/r, Darunavir/r
  • A NNRTI: efavirenz
  • integrase inhibitor: Raltegravir, dolutegravir, Elvitegravir
38
Q

How do you prevent and management HIV drug resistance?

A
  • adherence is Critical. When inadequately suppressive regimens are used, virus will mutate and become resistant to 1+ drug in regiment. Adding single drugs to failing regimens will cause more resistance–>multi drug resistance
  • Use adherence aids: treat psychiatric and substance abuse co morbidities, education, peer support, stable living situation, family support, simple regiment, etc.

Hematology (29 decks)

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