HIV

what was AIDS formerly called

GRID

how is HIV transmitted

birth, heterosexually, blood products

total deaths of HIV/AIDS

36 million

how many have access to cART

75%

how many people have lived with HIV

78 million

how many times have HIV-1 jumped to humans?

4 different occassions

lentivirus

slow virus that infects dividing and non-dividing cells

HIV family

retroviridae

how does HIV differ from other retroviruses

other retroviruses can only infect dividing cells

3 necessary genes of retrovirus

gag, pol, env

gag gene

structural proteins

pol gene

enzymes

env gene

membrane glycoproteins

what proteins do lentiviruses have

auxiliary proteins

auxiliary proteins

increases replicative fitness

HIV regulatory auxiliary proteins

Tat, Rev

HIV accessory auxiliary proteins

Vif, Vpu, Nef

what does env gene encode

surface and transmembrane glycoproteins

what does gag encode

matrix, nucleocapsid, and capsid (structural proteins)

what does pol encode

IN, PR, RT (enzymes)

regulatory proteins increase what?

efficiency

accessory proteins increase what?

pathology

HIV fusion peptide

gp41 and gp120

what occurs upon CD4 binding?

conformational change in gp120 that then binds CCR

what happens when gp120 binds CCR

another conformational change that exposes the fusion peptide

what are determinants of HIV tropism

CD4 and CCR (either CCR5 or CXCR4)

R5-topic features

T-cells have more CCR5 than CXCR4 so it is more widespread, infects active T-cells, easier to transmit

X4-tropic features

less effective, infects naive T-cells, occurs in later HIV

M-tropic features

macrophage, CCR5 users, does not have as much CD4

transmitted/founder viruses

viruses that are preferentially transmitted and establish infection in humans

what tropism are founder viruses usually

R5 but not M-tropic

CCR5 delta32 mutation

protects against HIV-1 infection in 4-16% of European descent and homozygous in 1% of humans

what mediates HIV transcription of provirus

RNA pol II or DdRP

Tat

transactivator of transcription that binds to a sequence

TAR

trans-activating response element (Sequence)

what occurs when Tat binds to TAR RNA

stimulates processivity of transcription by RNA pol II

what happens to non-spliced RNA

it leaves the cell and binds Rev/RRE via a nuclear export signal (Leu-rich)

what is unique to Tat

recognition of a viral transcriptional control sequence as RNA

what does Tat enhance

elongation

what does it mean for murine CycT1 that it does not support Tat-dependent enhancement

must change CycT1 and CD4 to use mice as HIV-models

what happens when Tat binds to TAR?

RNA is made as full-length

important HIV accessory proteins

Vif, Vpu, Nef

how do Vif, Vpu, and Nef work

antagonists of cellular intrinsic defense mechanisms and adapter proteins that facilitate degradation of antiviral host proteins

Vif

viral infectivity factor that is cell-type-specific

does Vif expression in target cells rescue Vif(-) virus

no, must be in virus-producing cell

what does it mean for Vif to be cell-type specific

Vif(-) viruses made by some cell lines are not infectious (non-permissive)

can virions from non-permissive cells infected by Vif(-) complete reverse transcription?

no, no detectable dsDNA

what happens when permissive cell line is infected with WT or Vif(-) virus

infectious progeny is made

what happens when non-permissive cell line is infected with WT and Vif(-) virus?

WT creates infectious progeny while Vif(-) does not

heterokaryon

fusion of two cell types with both cell nucleus types in it

what happens when Vif(-) infects heterokaryon

non-infectious progeny are made

what do non-permissive cells express

antiviral factor called APOBEC3G

what does Vif mediate

association of APOBEC3 with ubiquitination machinery for degradation

APOBEC3

cytidine deaminase that is packaged into virions that binds viral gRNA and blocks reverse transcription and creates C→U mutations in cDNA and G→A mutations in dsDNA

what happens in Vif+, APOBEC3G+ cell

normal reverse transcription

what happens in Vif-, APOBEC3G+ cell

DNA synthesis inhibition and mutagenesis

what does Vif link?

A3G to ubiquitin-proteasome pathway and facilitates degradation of A3G

absence of Vpu

virus particle release fails in cell type specific manner

tetherin/BST-2

tethers nascent particles of enveloped viruses to PM (inhibits release of enveloped viruses)

HIV antagonist of tetherin/BST-2

Vpu

tetherin/BST-2 viral antagonists

sequester or degrade BST-2/tetherin

what does Vpu downregulate

tetherin and CD4

what does downregulation of CD4 do

prevents sequestration of Env and facilitates virus release

what does Nef downregulate

CD4 and MHC-1 so CD8 cells are not made

what does Nef promote

degradation of SERINC5

SERINC5

incorporated into virions to inhibit virus entry

routes of HIV transmission

sex, needle sharing, mother-to-child

highest titer of virus is found

blood, genital secretions, breast milk

low/no titers found in

saliva, sweat, urine, tears, mosquitoes

what inactivates HIV

heat, bleach, alcohol

initial HIV spread

crosses mucosal barrier and infects activated and resting CD4 T-cells that migrate to lymph nodes and GALT

acute phase

30-60% of CD4 T-cells in gut die, propagation suppressed by CTL, memory T-cells become latent reservoir

asymptomatic phase

slow CD4 T-cell decline, low-rate propagation in lymph nodes, propagation suppressed by CTL, increased viral diversity

symptomatic phase and AIDS

increased propagation, lymphoid tissue destroyed, CXCR4 predominates, CTL decline, opportunistic infection

rapid progressor

progress to AIDS in 2-3 years (10%)

typical progession

80% show progression and 50% get AIDS by 10 years

long-term nonprogressor

under 5% remain AIDS free for many years

why the variability of response?

other infections, genetic factors, viruses with deletions in nef gene so adaptive immunity is less effective

minimum rate of HIV release

10^10 virions per day or one cycle of replication per infected cell per day

where does most of the virus in the blood come from

infected activated CD4 T-cells

where does some of the virus in blood come from

macrophages and latently-infected, nonactivated T-cells

what does complete eradication require

proviruses to be eliminated from longer living cells

HIV effects on lymph nodes

most virus-producing cells, destruction of germinal centers

neurological effects

encephalitis, AIDS-related dementia, neurons killed by cytokines and viral proteins

gut effects

Th17 cells impaired, loses barrier function, malnutrition

AZT

first licensed drug that is a nucleoside analog inhibitor of RT that acts as a chain terminator and competes with cellular dNTPs

when is AZT used

monotherapies like prophylaxis before needle sticks or delivery

how did drug resistance occur in AZT

single base pair change in 1/4 sites in RT gene

intermediate dose

drug is working but inhibition not complete so mutants emerge

optimal dose

drug blocks reproduction completely

6 classes of HIV inhibitors

capsid, RT, PR, IN, fusion, attachment

cART

combination anti-retroviral therapy with 3 or 4 anti-HIV drugs

pros of cART

reduction in drug resistance and transmission rate and longer and more normal life

cons of cART

expensive, side effects, noncompliance

how is cART given

once a day single pills in clinic

goals in HIV/AIDS research

address drug resistance, vaccines for prevention (broadly neutralizing Ab or BNAb), and cure

why is there not a vaccine yet?

many variants, can remain as silent provirus that is invisible, gp120 mutates and makes Abs lose potency

current approach for prevention

PrEP and cART

strategies for cure

use gene therapy to block or mutate expression of CCR5 gene or express bNAbs in infected people

cure

eliminating replication-competent HIV