HIV Flashcards
HIV-1
similar to SIV of chimpanzees
HIV-2
similar to SIV of sooty mangabeys, less prevalent,
SIV
endemic in many nonhuman primate species in Africa,
nonpathogeic in natural host but maintain high virus loads
less immune activation in natural host
Clades
virus is different in different geographic areas
primary HIV infection
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
how to detect virus
- viral RNA PCR first
- ELISA
- Western blot - anti-virus antibody
Sexual Transmission of HIV
- cell free or cell associated virus in semen/mucosal surface attaches to dendritic cells (R5)
- DCs hand off virus to CD4+ T cells
- Transport of virus to regional lymphnoes - CD4 T cells and macrophages are infected in draining lymph nodes
- Entry of virus infected cells into blood stream
- T cells are depleted and virus is disseminated systemically
AIDS disease course
- primary infection
- acute phase - decrease in T cells, increase in viral load, acute HIV syndrome, wide dissemination of virus
- chronic phase - virus decreased by CTLs and Abs, T cell count goes up and stays steady (clinical latency)
- AIDS - constitutional symptoms, opporutnistic disease, increase in viral load and decrease in CD4
viral load setpoint
determines rate of disease progression
- progressors - 1-2 years, never in control of virus
- long-term non progressors - may never get sick
- elite controlers - limit of detection of viral dna
How HIV causes AIDS
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
HIV glycoprotein
gp120, gp41
HIV genome
postive sense ssRNA
structural proteins:
gag - matrix, capsid, nucleocapsid, p6
pol - protease, RT, integrase
Env: gp160 –> gp 120, gp41
cleaved into invididual genes
HIV lifecycle
- attachment/fusion
- uncoating
- RT - RNA to DNA in cytosol
- DNA into nucleus and integrated into host chromosome
- transcription of mRNA
- translation of mRNA in cytosol
- assembly and budding
- cleavage of all proteins into mature
HIV Receptor
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
d32 ccr5
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
coreceptor switching
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!
Miraviroc
CCR5 antagonist
virus mutates to using CXCR4 quickly but works in patients with viruses using CCR5
APOBEC3
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
VIF
small protein encoded by vif gene in virus
prevents APOBEC3G from attacking viral DNA
latent resevoir
once HIV DNA integrated into host DNA - infective - can become “latent” - therapy can’t kill it!
zinc finger nucleases
sequence-specific molecular scissors that cut dsDNA
gene therapy - target CCR5 and cut out gene in cell
NRTIs
nucleotide RT inhibitors
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!
NRTI toxicity
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!)
NNRTIs
noncompetitive binding to RT without intracellular conversion
cross resistance within class
NNRTI toxicity
first gen: liver failure
CNS
dyslipidemia
Vit D
second gen:
rash, hepatic, headache
fewer side effects
Resistance to NNRTIs
resistance mutation to one NNRTI –> cross resistance
use second gen drugs
Protease Inhibitors
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
PI toxicities
hyperlipidemia (increase Ch, LDL, TG - cardio events)
insulin resistance, hyperglycemia, diabetes
lipodistrophy - fat redistrabution, loss in face
hepatic
bone loss
Resistance to PIs
initial resistance may be unique to specific drug
over time - accumulate - greater resistance
longer therapy - cross resistance!
Fusion inhibitor
synthetic peptide that binds gp41 of envelope gp - blocks conformational changes required for viral and cell membranes
subcutaneous only
patients don’t like it
chemokine receptor antagonist
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
integrase inhibitor
block early stage in integration of virus DNA into host DNA
resistance !
integrase inhibitor toxicitiy
rhabdomyolysis - break muscles - muscle enzymes, renal failure
ARV boosting
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
incomplete suppression
drug pressure, inconsistent adherence
select for mutants
Durable suppression
kill off most viruses, no resistance bc killing all
viral load
speed
plasma RNA levels - magnititude of viral rep is related to rate of disease progresion and time to death
CD4 Count
extent of immune damage - correlates with risk of opportunistic infections and time to death
INSTI-based regiments
integrase based - with 2 more drugs for resistance
PI-based regiments
boosted! with 2 other PI drugs
recomended initial regimens
INSTI - integrase
PI - protease inhibitor
genoytypic drug resistance
changes in genome that appear as a consequence of drug exposure
easy to preform hard to interpret
phenotypic drug resistance
virus grows in culture despite presence of drug
takes a long time but easy to interpret
Clinical drug resistance
lack of benefit from drug - not durably suppressed
PEP
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
PrEP
reduction of HIV in high risk populations
take it daily
risk reduction counsling and StD testing
