Viral Pathogenesis-HIV Flashcards

1
Q

Model of HIV

A
  • 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
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2
Q

HIV Virion Proteins (3)

A
  • 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)
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3
Q

Regulatory Auxiliary Proteins of HIV (2)

A
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
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4
Q

Accessory Auxiliary Proteins of HIV (4)

A
  • nef
  • vif
  • vpr
  • vpu
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5
Q

Accessory Auxiliary Proteins of HIV-nef

A
  • negative reg. factor
  • can increase or decrease virus infectivity
  • downregs MHC-1, CD4, CD8
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6
Q

Accessory Auxiliary Proteins of HIV-vif

A
  • virion infectivity factor
  • causes proteosomal degradation of cell APOBEC3G (cytidine deaminase which converts C to U and hyper mutates nascent minus strand reverse transcripts)
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7
Q

Accessory Auxiliary Proteins of HIV-vpr

A
  • viral protein R
  • weak Tc activator
  • causes G2 arrest (activates p21 cyclin-dependent kinase inhibitor)
  • facilitates nuclear entry of preinteg complex
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8
Q

Accessory Auxiliary Proteins of HIV-vpu

A
  • 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
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9
Q

Consequences of HIV infection on host cell gene expression

A
  • 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)
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10
Q

Progression to AIDs

A
  • 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
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11
Q

AIDs defining infections

A
  • pneumonia (often parasitic)
  • toxoplasmosis (parasitic infection of the brain)
  • cryptosporidium (parasitic infection of intestinal tract)
  • herpes virus infections (HSV, CMV)
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12
Q

CD4 cell infection/depletion

A
  • 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
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13
Q

Receptors for HIV

A

-CD4 present on CD4 T helper cells and macrophages

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14
Q

Chemokine Receptor Usage-CCR5

A
  • 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
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15
Q

Chemokine Receptor Usage-CXCR4

A
  • 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)
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16
Q

CCR5 mutant individuals

A
  • 32 bp deletion results in nonfunctional receptor

- resist M-tropic but not T-tropic

17
Q

CXCL12 (SDF-1) mutant individuals

A
  • delayed onset of AIDS

- restrict T tropic HIV

18
Q

Increased Levels of circulating chemokines-role in resistance to HIV

A
  • CCL3, 4, 5 block M tropic HIV

- CXCL12 blocks T tropic HIV

19
Q

M-tropic HIV (R5)

A
  • infects macrophages and CD4+ t cells
  • overtime replaced w/ t-tropic
  • uses CCR5 as receptor
20
Q

T-tropic HIV (X4)

A
  • able to induce fusion b/w 2 cells
  • occurs late in infection
  • uses CXCR4 as receptor
21
Q

Progression from R5 to X4

A
  • 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
22
Q

Antiviral Strategies against HIV (8)

A
  • 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)