Flashcards in Wk16D2 HIV Deck (24):
HIV-1 basics (family, genome, capsid, size)
Retrovirus (+ strand RNA)
Complex genome (add'n regulatory proteins)
100 nm diameter
All retroviruses contain these 3 genes
gag, pol, env
HIV contains these 6 additional regulatory genes
tat (binds Tat activating region, tx activation)
rev (binds rev responsive element, nuc export)
nef (neg factor, MHC downreg etc)
vpr (cell cycle regulator)
vpu (CD4 degradation)
vif (degrades editing enzyme Apobec3G)
MA (matrix - underlies membrane)
CA (capsid - cone shape
NC (nucleocapsid - binds genomic RNA)
Think MaCaNac island
viral enzymes within virion (drug targets):
RT (reverse transcriptase)
surface glycoproteins for binding and entry
SU (gp120 - binding CD4 cytokine co-receptors)
TM (gp41 - fusion with host cell membrane)
How does HIV enter cell? What drug targets this?
Knob (3x SU + TM) binds CD4, then co-receptor CCR5 or CXCR4, lipid envelope fuses.
Maraviroc blocks CCR5/HIV interaction
How does T20/enfuvirtide act?
Inhibits fusion by binding TM/gp41 as it inserts itself into host cell membrane
What are 10 steps of virus infection (when virus meets host cell)?
Binding, Co-receptor binding, Fusion, Uncoating, Reverse transcription
Pre-initiation complex, Integration, Cellular Transcription, Viral assembly, Budding
What is lost during uncoating?
Matrix is lost after it and viral core are deposited into cytoplasm. RT can begin.
What are NRTI's? Examples?
Nucleoside analog RT Inhibitors (AZT, ddl, 3TC)
Non-Nucleoside RTI's (Nevirapine, Efavirenz)
Where does pre-integration complex migrate?
To nucleus with localization signals. Contains 2(!?) copies of RNA genome.
Where does Raltegravir (Isentress) act?
Integration. Completed viral DNA has flanking long terminal repeats (LTR), and integrase inserts it into host genome.
What splicing trickery ensues after integration? How is rev involved?
RNA is unspliced, singly spliced, or multi-spliced. Initially only multispliced are translated, making Tat, Rev, Nef. Rev binds RRE's to export larger mRNAs.
How does viral assembly occur? How are glycoproteins made?
Self-assembly? Not understood. gp160 cleaved to gp120 and gp41.
How do protease inhibitors work? Examples?
Nelfinavir, Ritonavir, Indinavir (NavIR's)
Protease catalyzes post-budding maturation by allowing capsid condensation.
What is viral set point? What is its clinical importance?
The level at which viral load in plasma is maintained AFTER initial peak of viremia. Prognostic. 10^4-5 copies/mL plasma is intermediate range.
What defines AIDS as opposed to merely HIV+? How long do untreated AIDS patients have?
AIDS is presence of one of the opportunistic infections or neoplasms OR <200 CD4+ T cells/uL.
Typically fatal within 1 yr if untreated.
What's the unplugged, half-full sink with water running analogy?
Pool of CD4+ T cells during latent infection. Tap is Thymus, but can be "shut off". Drain opens wider with increasing viral load.
What other cells are affected in AIDS?
Random cells through cytokine imbalance and tissue destruction.
What is the most variable HIV protein? What is the clinical significance of tropism?
SU gp120 has 5 variable regions. V3 primarily determines host cell interaction. CXCR4 tropism is related to AIDS progression, while CCR5 tropism related to initial infection.
How do Class-I HLA and CCR5 genes play a role in HIV infection?
Certain HLA forms present better than others, and can define Elite Controllers vs susceptible (often homozygous).
CCR5del32 confers resistance
How does HIV mutate so readily?
How does it evade antibodies?
How does it evade NK cells?
How does it kill CTLs?
Constant pool of mutant viruses: Short replication cycle (1.5 days), High viral load (10^9 made /day), Error prone RT (error every third genome)
gp120/41 not immunogenic (sterics/mimicry)
Downreg MHC-I A+B but not C