Viral Pathogenesis-HIV

Question 1

Model of HIV

Answer 1

• diploid genome, occupies the core w/ other proteins and enzymes involved in rep
• HIV-1 (dominant, vpu is only in HIV1) and HIV-2
• small ORFs that give rise to accessory proteins

Question 2

HIV Virion Proteins (3)

Answer 2

• gag: group specific antigens (core proteins p24, p17, p9, p7)
• pol: polymerase (RT and integrase)
• env: envelope-gp160 cleaved to gp120 (receptor binding) and gp41 (fusion)

Question 3

Regulatory Auxiliary Proteins of HIV (2)

Answer 3

tat
-transactivator of Tc
-enhances Tc, binds TAR in LTR
-decreases Tc of cell genes (eg. MHCII)
rev 
-regulator of virion proteins 
-binds RRE (rev responsive element)-facilitates nuclear export of unspliced and partly spliced RNA

Question 4

Accessory Auxiliary Proteins of HIV (4)

Answer 4

• nef
• vif
• vpr
• vpu

Question 5

Accessory Auxiliary Proteins of HIV-nef

Answer 5

• negative reg. factor
• can increase or decrease virus infectivity
• downregs MHC-1, CD4, CD8

Question 6

Accessory Auxiliary Proteins of HIV-vif

Answer 6

• virion infectivity factor
• causes proteosomal degradation of cell APOBEC3G (cytidine deaminase which converts C to U and hyper mutates nascent minus strand reverse transcripts)

Question 7

Accessory Auxiliary Proteins of HIV-vpr

Answer 7

• viral protein R
• weak Tc activator
• causes G2 arrest (activates p21 cyclin-dependent kinase inhibitor)
• facilitates nuclear entry of preinteg complex

Question 8

Accessory Auxiliary Proteins of HIV-vpu

Answer 8

• viral protein U
• integral membrane glycoprotein mainly in ER/golgi
• disrupts env-CD4 complex-promotes CD4 degradation
• promotes budding, likely by removing CD4 trap in ER, allowing gp160 maturation
• antagonizes tetherin (binds newly produced viruses to cell to prevent spreading), allowing virus release from cell surface

Question 9

Consequences of HIV infection on host cell gene expression

Answer 9

• activation of cell Tc factors, gene expression
• integrated HIV DNA contains binding sites for cell Tc factors (eg. SPI, NF-kappaB, AP-1, NFAT-1)
• TAR element binds Tat
• NF-kappaB binding site: NK-kappaB stimulated by mitogens, cytokines
• upregulates Tc of all genes w/ NF-kappaB elements (IL-2, IL-2R, HIV)

Question 10

Progression to AIDs

Answer 10

• progressive course of declining immunity
• gradual decrease in CD4 pos. cells
• increased viral, bacterial and parasitic infection
• 1st symptoms are skin infections (bacterial, viral, fungal)
• later AIDs defining infections

Question 11

AIDs defining infections

Answer 11

• pneumonia (often parasitic)
• toxoplasmosis (parasitic infection of the brain)
• cryptosporidium (parasitic infection of intestinal tract)
• herpes virus infections (HSV, CMV)

Question 12

CD4 cell infection/depletion

Answer 12

• mucosal HIV infection results in drastic depletion of mucosal CD4 cells (effect on peripheral CD4 cells much less severe)
• CCR5+ memory T cells targeted for HIV infection and depletion
• CD4 cell depletion due to direct virus infection and virus induced Fas-mediated apoptosis

Question 13

Receptors for HIV

Answer 13

-CD4 present on CD4 T helper cells and macrophages

Question 14

Chemokine Receptor Usage-CCR5

Answer 14

• present on macs, Th cells, esp. memory T cells
• receptor for beta-chemokines (MIP-1alpha-CCL3, MIP-1beta-CCL4, RANTES-CCL5)
• used by M-tropic (R5) and T-tropic (X4) HIV

Question 15

Chemokine Receptor Usage-CXCR4

Answer 15

• fusin
• on macs, Th cells esp naive T cells
• receptor for stromal derived factor, SDF-1 (CXCL12)
• present on more cell types than CCR5
• used by T-tropic HIV (X4)

Question 16

CCR5 mutant individuals

Answer 16

• 32 bp deletion results in nonfunctional receptor

- resist M-tropic but not T-tropic

Question 17

CXCL12 (SDF-1) mutant individuals

Answer 17

• delayed onset of AIDS

- restrict T tropic HIV

Question 18

Increased Levels of circulating chemokines-role in resistance to HIV

Answer 18

• CCL3, 4, 5 block M tropic HIV

- CXCL12 blocks T tropic HIV

Question 19

M-tropic HIV (R5)

Answer 19

• infects macrophages and CD4+ t cells
• overtime replaced w/ t-tropic
• uses CCR5 as receptor

Question 20

T-tropic HIV (X4)

Answer 20

• able to induce fusion b/w 2 cells
• occurs late in infection
• uses CXCR4 as receptor

Question 21

Progression from R5 to X4

Answer 21

• R5 infects macrophages and memory CD4+ t cells
• dual tropic/mixed virus populations can use both CCR5 and CXCR4
• X4 occurs at late stages of disease, infects macs, naive, memory CD4 t cells
• naive CD4 t cells lack CCR5

Question 22

Antiviral Strategies against HIV (8)

Answer 22

• receptor blockers (soluble CD4, chemokines, chemokine analogues which bind to CCR)
• viral entry (membrane fusion blockers)
• RT inhibitors* (AZT acts as chain terminator)
• accessory protein inhibitors (e.g. vif)
• integrase inhibitors*
• mRNA inhibitors
• protease inhibitors*
• combination therapy (to resist HIV mutations, antiviral resistance)