Wk16D2 HIV

Question 1

HIV-1 basics (family, genome, capsid, size)

Answer 1

Enveloped
Retrovirus (+ strand RNA)
Complex genome (add'n regulatory proteins)
Cone-shaped capsid 
100 nm diameter

Question 2

All retroviruses contain these 3 genes

Answer 2

gag, pol, env

Question 3

HIV contains these 6 additional regulatory genes

Answer 3

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)
Think VVVTRaiN

Question 4

gag

Answer 4

structural proteins: 
MA (matrix - underlies membrane)
CA (capsid - cone shape
NC (nucleocapsid - binds genomic RNA)
Think MaCaNac island

Question 5

pol

Answer 5

viral enzymes within virion (drug targets):
IN (integrase)
PR (protease)
RT (reverse transcriptase)
Think INterPReRT

Question 6

env

Answer 6

surface glycoproteins for binding and entry
SU (gp120 - binding CD4 cytokine co-receptors)
TM (gp41 - fusion with host cell membrane)

Question 7

How does HIV enter cell? What drug targets this?

Answer 7

Knob (3x SU + TM) binds CD4, then co-receptor CCR5 or CXCR4, lipid envelope fuses.
Maraviroc blocks CCR5/HIV interaction

Question 8

How does T20/enfuvirtide act?

Answer 8

Inhibits fusion by binding TM/gp41 as it inserts itself into host cell membrane

Question 9

What are 10 steps of virus infection (when virus meets host cell)?

Answer 9

Binding, Co-receptor binding, Fusion, Uncoating, Reverse transcription
Pre-initiation complex, Integration, Cellular Transcription, Viral assembly, Budding

Question 10

What is lost during uncoating?

Answer 10

Matrix is lost after it and viral core are deposited into cytoplasm. RT can begin.

Question 11

What are NRTI’s? Examples?

NNRTI’s?

Answer 11

Nucleoside analog RT Inhibitors (AZT, ddl, 3TC)

Non-Nucleoside RTI’s (Nevirapine, Efavirenz)

Question 12

Where does pre-integration complex migrate?

Answer 12

To nucleus with localization signals. Contains 2(!?) copies of RNA genome.

Question 13

Where does Raltegravir (Isentress) act?

Answer 13

Integration. Completed viral DNA has flanking long terminal repeats (LTR), and integrase inserts it into host genome.

Question 14

What splicing trickery ensues after integration? How is rev involved?

Answer 14

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.

Question 15

How does viral assembly occur? How are glycoproteins made?

Answer 15

Self-assembly? Not understood. gp160 cleaved to gp120 and gp41.

Question 16

How do protease inhibitors work? Examples?

Answer 16

Nelfinavir, Ritonavir, Indinavir (NavIR’s)

Protease catalyzes post-budding maturation by allowing capsid condensation.

Question 17

What is viral set point? What is its clinical importance?

Answer 17

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.

Question 18

What defines AIDS as opposed to merely HIV+? How long do untreated AIDS patients have?

Answer 18

AIDS is presence of one of the opportunistic infections or neoplasms OR <200 CD4+ T cells/uL.
Typically fatal within 1 yr if untreated.

Question 19

What’s the unplugged, half-full sink with water running analogy?

Answer 19

Pool of CD4+ T cells during latent infection. Tap is Thymus, but can be “shut off”. Drain opens wider with increasing viral load.

Question 20

What other cells are affected in AIDS?

Answer 20

Microglia/Astrocytes (NeuroAIDS)

Random cells through cytokine imbalance and tissue destruction.

Question 21

What is the most variable HIV protein? What is the clinical significance of tropism?

Answer 21

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.

Question 22

How do Class-I HLA and CCR5 genes play a role in HIV infection?

Answer 22

Certain HLA forms present better than others, and can define Elite Controllers vs susceptible (often homozygous).
CCR5del32 confers resistance

Question 23

How does HIV mutate so readily?
How does it evade antibodies?
How does it evade NK cells?
How does it kill CTLs?

Answer 23

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

FasL induction

Question 24

What explains such long-term HIV infections?

Answer 24

It got into memory cells :(