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
