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EXAM 5 > HIV > Flashcards

HIV Flashcards

1
Q

HIV-1

A

similar to SIV of chimpanzees

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2
Q

HIV-2

A

similar to SIV of sooty mangabeys, less prevalent,

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3
Q

SIV

A

endemic in many nonhuman primate species in Africa,

nonpathogeic in natural host but maintain high virus loads

less immune activation in natural host

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4
Q

Clades

A

virus is different in different geographic areas

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5
Q

primary HIV infection

A

fever, fatigue, rash, sore throat - some asymptomatic

5-21 days post-exposure - lasts 14d

patient is ab negative for weeks

very high virus levels

ab-positive in 3-4 wks

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6
Q

how to detect virus

A
  1. viral RNA PCR first
  2. ELISA
  3. Western blot - anti-virus antibody
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7
Q

Sexual Transmission of HIV

A
  1. cell free or cell associated virus in semen/mucosal surface attaches to dendritic cells (R5)
  2. DCs hand off virus to CD4+ T cells
  3. Transport of virus to regional lymphnoes - CD4 T cells and macrophages are infected in draining lymph nodes
  4. Entry of virus infected cells into blood stream
  5. T cells are depleted and virus is disseminated systemically
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8
Q

AIDS disease course

A
  1. primary infection
  2. acute phase - decrease in T cells, increase in viral load, acute HIV syndrome, wide dissemination of virus
  3. chronic phase - virus decreased by CTLs and Abs, T cell count goes up and stays steady (clinical latency)
  4. AIDS - constitutional symptoms, opporutnistic disease, increase in viral load and decrease in CD4
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9
Q

viral load setpoint

A

determines rate of disease progression

  1. progressors - 1-2 years, never in control of virus
  2. long-term non progressors - may never get sick
  3. elite controlers - limit of detection of viral dna
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10
Q

How HIV causes AIDS

A

virus kills CD4 T cells, depletes Thelper cells (B and CTL can’t respond!)

virus attacks Th cells that respond to it

generalized CD4 depletion - can’t respond to pathogens - opportunistic infections

Th cells are replenished from bone marrow stem cells but with time these become exhausted - CD4 cell crash

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11
Q

HIV glycoprotein

A

gp120, gp41

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12
Q

HIV genome

A

postive sense ssRNA

structural proteins:

gag - matrix, capsid, nucleocapsid, p6

pol - protease, RT, integrase

Env: gp160 –> gp 120, gp41

cleaved into invididual genes

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13
Q

HIV lifecycle

A
  1. attachment/fusion
  2. uncoating
  3. RT - RNA to DNA in cytosol
  4. DNA into nucleus and integrated into host chromosome
  5. transcription of mRNA
  6. translation of mRNA in cytosol
  7. assembly and budding
  8. cleavage of all proteins into mature
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14
Q

HIV Receptor

A

requrires 2 cell surface proteins

Receptor: CD4

CoReceptor: CCR5 or CXCR4 (chemokine GPCR for chemotaxis

Entry: CD4 binding –> opens and exposes CoR bind site –> bind coR and virus/cell fuse

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15
Q

d32 ccr5

A

genetic defect that protects against HIV

32 bp deletion in ccr5 that encodes a truncated ccr5

homozygotes are resistant to HIV infection, hets not protected but takes longer to develop AIDS

no effect on health

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16
Q

coreceptor switching

A

viruses use CCR5 only early in infection

later, viruses appear that use CXCR4, allows them to infect a larger numer target cells because it’s mroe widely expressed on Th cells

mutations in gp120!

drugs that target CCR5 - virus switch to CXCR4!

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17
Q

Miraviroc

A

CCR5 antagonist

virus mutates to using CXCR4 quickly but works in patients with viruses using CCR5

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18
Q

APOBEC3

A

potent arm of innate immune system

cytidine deaminase - changes C to U in ssDNA

in host cell - signals for the cell to chop up all DNA with a U - kills virus

VIF - binds apobec3 and sends it to proteasome

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19
Q

VIF

A

small protein encoded by vif gene in virus

prevents APOBEC3G from attacking viral DNA

20
Q

latent resevoir

A

once HIV DNA integrated into host DNA - infective - can become “latent” - therapy can’t kill it!

21
Q

zinc finger nucleases

A

sequence-specific molecular scissors that cut dsDNA

gene therapy - target CCR5 and cut out gene in cell

22
Q

NRTIs

nucleotide RT inhibitors

A

converted intracellularly to TriPO4 - competatively inhibits RT by acting as alternate substrate

Azide group (N3) instead of hydroxal (OH) on pentose sugar

once it binds to OH of last nt - no more can attach 0 incomplete proviirus!

23
Q

NRTI toxicity

A

lactic acidosis - mitochondrial damage (increased lactate and decreased pH, nausea, death)

anemia - AZT

hypersensitivity - with certain HLA - possible risk of MI

Renal failure - effect on kidneys (Tenofovir!)

24
Q

NNRTIs

A

noncompetitive binding to RT without intracellular conversion

cross resistance within class

25
Q

NNRTI toxicity

A

first gen: liver failure

CNS

dyslipidemia

Vit D

second gen:

rash, hepatic, headache

fewer side effects

26
Q

Resistance to NNRTIs

A

resistance mutation to one NNRTI –> cross resistance

use second gen drugs

27
Q

Protease Inhibitors

A

protease enzyme cleaves HIV precursor proteins (gag/pol) into active proteins

PIs bind to protease and prevent cleavage/inhibit assembly of new NIV viruses

non infectious virions produced

28
Q

PI toxicities

A

hyperlipidemia (increase Ch, LDL, TG - cardio events)

insulin resistance, hyperglycemia, diabetes

lipodistrophy - fat redistrabution, loss in face

hepatic

bone loss

29
Q

Resistance to PIs

A

initial resistance may be unique to specific drug

over time - accumulate - greater resistance

longer therapy - cross resistance!

30
Q

Fusion inhibitor

A

synthetic peptide that binds gp41 of envelope gp - blocks conformational changes required for viral and cell membranes

subcutaneous only

patients don’t like it

31
Q

chemokine receptor antagonist

A

miraviroc

prevents infection of cd4 t cells by blocking ccr5 R (present early in infection)

strain but be ccr5 to be effective

liver/heart toxicity

drug drug interactions

32
Q

integrase inhibitor

A

block early stage in integration of virus DNA into host DNA

resistance !

33
Q

integrase inhibitor toxicitiy

A

rhabdomyolysis - break muscles - muscle enzymes, renal failure

34
Q

ARV boosting

A

certain (PIs a lot!) have drug-drug interactions

boost of PIs - use small dose of ritonavir or another “booster to enhance exposure through inhibition of CYP450!

enhance level of major drug - increase serum levels and use less

improved drug levels - improve efficacy, decrease pill burden, reduce resistance

35
Q

incomplete suppression

A

drug pressure, inconsistent adherence

select for mutants

36
Q

Durable suppression

A

kill off most viruses, no resistance bc killing all

37
Q

viral load

A

speed

plasma RNA levels - magnititude of viral rep is related to rate of disease progresion and time to death

38
Q

CD4 Count

A

extent of immune damage - correlates with risk of opportunistic infections and time to death

39
Q

INSTI-based regiments

A

integrase based - with 2 more drugs for resistance

40
Q

PI-based regiments

A

boosted! with 2 other PI drugs

41
Q

recomended initial regimens

A

INSTI - integrase

PI - protease inhibitor

42
Q

genoytypic drug resistance

A

changes in genome that appear as a consequence of drug exposure

easy to preform hard to interpret

43
Q

phenotypic drug resistance

A

virus grows in culture despite presence of drug

takes a long time but easy to interpret

44
Q

Clinical drug resistance

A

lack of benefit from drug - not durably suppressed

45
Q

PEP

A

post exposure prophylaxis

needlesticks, mucocutaneous exposure, sexual assault

factors: deep injury, hollow needle, terminal aids

baseline HIV test - initate immediately for 28 dayys

with counsling

AZT prevents transmission mother to to infant

46
Q

PrEP

A

reduction of HIV in high risk populations

take it daily

risk reduction counsling and StD testing

EXAM 5 (11 decks)

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