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CMBM Exam 4 > HIV > Flashcards

HIV Flashcards

1
Q

HIV-1

A
  • Responsible for most cases of AIDS in the US
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2
Q

Antigenicically disntinct genotypes of HIV-1

A
  • Groups M, O, N, P
  • Group M is responsible for the global AIDS epidemic
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3
Q

Group M HIV genotype

A
  • Based on sequence differences of env and gag genes
  • results in antigenicity differences b/w gp120 and capsid proteins
  • Subtype B predominates in US
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4
Q

Clades definition

A
  • Varying subtypes of a gene
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5
Q

Essential genes (all retroviruses)

A
  • gag (group antigens) gene
  • pol (polymerase) gene
  • env (envelope) gene
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6
Q

Gag gene

A
  • Essential gene of retroviruses
  • Encodes:

*matrix protein (p17)

*capsid protein (p24)

*nucleocapsid (p9)

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7
Q

Pol gene

A
  • Essential gene of retroviruses
  • Encodes:

*protease (p10)

*reverse transcriptase (p50)

*RNase (p15)

*integrase (p31)

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8
Q

Env gene

A
  • Essential gene of retroviruses
  • Encodes:

*surface subunit (gp120)

*transmembrane subunit (gp41)

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9
Q

HIV regulatory (accessory) genes

A
  • tat
  • rev
  • nef
  • vif
  • vpu
  • vpr
  • These genes enhance the replication and infectivity to counter some host defense mechanisms
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10
Q

Tat gene

A
  • HIV regulatory gene
  • transactivates transcription of HIV genes
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11
Q

Rev gene

A
  • HIV regulatory gene
  • regulates RNA splicing and promotes export of mRNA to the cytoplasm
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12
Q

Nef gene

A
  • HIV regulatory gene
  • Reduces cell surface expression of CD4 and MHC class I; alters T cell signaling pathways; required to maintain high viral loads; essential for progression to AIDS
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13
Q

Vif gene

A
  • HIV regulatory gene
  • Promotes assembly; blocks a cellular antiviral protein that produces hypermutations during cDNA transcription
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14
Q

Vpu gene

A
  • HIV regulatory gene
  • Facilitates release of virus by countering a cellular protein that tethers virions to the infected cell; induces degradation of cell surface CD4
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15
Q

Vpr gene

A
  • HIV regulatory gene
  • Transports cDNA to the nucleus; induces cell cycle arrest; facilitates replication in myeloid cells
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16
Q

Long Terminal Repeats (LTR)

A
  • On either end of the HIV genome
  • Contains promoters and sequences used as binding sites by transcription factors
  • Activated cells produce transcription factors that bind LTR and activate transcription of viral genes

- Activated T cells can be productively infected by HIV and generate progeny virions

- Resting T cells are not productively infected by HIV

*incomplete viral cDNA transcripts accumulate or

*proviral DNA is made but does not integrate into the host chromosome (pre-integration latency)

17
Q

HIV replication outline

A
  • Viral attachment and entry
  • Genomic RNA reverse transcribed into cDNA
  • cDNA enter the nucleus and integrates into host chromosomes
  • Transcription/translation of genes from the proviral DNA template
  • Assembly of a premature particle and budding through the plasma membrane
  • Maturation into infectious virus
18
Q

HIV Attachment and entry

A
  • Host cell receptors:

*CD4; primary co-receptor to HIV gp120

*chemokine receptors (CCR-5, CXCR-4); primary co-receptor to HIV gp120

*alpha-4 beta-7 integrin (GALT homing receptor for activated T-cells)

*DC-SIGN (intercellular adhesion molecule on dendritic cells)

  • Viral attachment

*gp120

  • Entry

*virus-cell fusion at the plasma membrane

*receptor-mediated endocytosis- fusion at the endosomal membrane

*mediated by gp41 (activated only when both co-receptors (CD4, chemokine) are bound by HIV ligand (gp120)

19
Q

Assembly and Maturation of HIV

A
  • Assembly at the cell surface

*gag and gag-pol polyprotein precursors package viral RNA genome

  • Budding through the cell membrane

*acquires lipid envelope w/gp120 and gp41

  • Maturation into infectious virus

*HIV protease cleaves gag and gag-pol polyprotein into individual proteins- changes the viral particle into a fully infectious one

*protease inhibitors inhibit this processing so mature proteins are not produced

20
Q

Classes of antiretrovirals

A
  • Nucleoside reverse transcriptase inhibitors (NRTIs); nucleoside analogues
  • Non-nucleoside reverse transcriptase inhibitors (NNRTI)
  • Protease inhibitors
  • Attachment/Entry inhibitors

*fusion inhibitors

*CCR5 inhibitor

  • Integrase inhibitors
21
Q

Nucleoside reverse transcriptase inhibitors

A
  • Zidovudine (azidothymidine or AZT)
  • Requires phosphorylation for activation

*cellular enzymes carry out all 3 phosphorylation steps

  • The activated drug binds to and inhibits RT
  • Incorporation into the DNA strand results in chain termination
  • Resistance is due to mutations in the HIV RT

*encoded by the pol gene

22
Q

Non-nucleoside reverse transcriptase inhibitors

A
  • Nevirapine
  • Does not require phosphorylation for activation
  • Bind to RT at a site distinct from the active site, but inhibit its activity
  • Inhibit HIV-1 RT, but not HIV-2 RT
  • Resistance is due to mutations in RT, distinct from those responsible for resistance to NRTIs
23
Q

Protease inhibitors

A
  • Saquinavir
  • Small molecules that bind in the enzymatic pocket of HIV protease
  • Inhibition of the protease inhibits the maturation of infectious viral particles
  • Resistance is due to mutations in the protease (pol gene)

*cross resistance b/w protease inhibitors is common

24
Q

Fusion inhibitors

A
  • Enfuvirtide
  • 36 amino acid peptide that binds to gp41
  • Blocks the conformational change that occurs after gp120 bind to CD4
  • gp41 is unable to mediate fusion b/w the viral envelope and the host cell membrane

*entry is inhibited

  • Resistance will occur if HIV mutates the binding site of enfuvirtide
25
Q

CCR5 inhibitor

A
  • Maraviroc
  • Binds CCR5 and alters its conformation
  • Inhibits HIV binding to CCR5
  • NOTE: this antiretroviral binds to a host protein
  • Mechanisms of resistance:

*HIV develops affinity for CXCR4 chemokine receptors

*pre-existing variants that use CXCR4 will be selected for

*HIV develops affinity for the drug-bound CCR5 conformation

26
Q

Integrase inhibitors

A
  • Raltegravir (Isentress and MK-0518)
  • MOA:

*integrase binds to the ends of the DNA provirus and helps to form the “preintegration complex” (PIC)

*it cleaves two nucleotides from each 3’ end of the provirus and then binds to host cell’s DNA

*it catalyzes a covalent joining (strand transfer) of the viral DNA 3’ ends to the cell’s DNA- inhibited by raltegavir

*the gaps are filled, presumably w/a host enzyme

27
Q

Points about antiretroviral therapy

A
  • Antiretroviral drugs disrupt productive infection, not latent
  • While antirretroviral therapy inhibits active viral replication, it provides selective pressure for drug resistance
  • Latency/sporadic reactivation from viral reservoirs makes it unlikely that HIV will be completely cleared from an infected individual

*multidrug resistance will not develop during latency

28
Q

HIV infection of CD4 T cells

A
  • Productive infection in activated CD4 T cells

*loss of CD4 T cells via direct HIV-induced cell lysis or apoptosis or CD8- mediated cell killing (1/2 life about 0.5 days)

  • Nonproductive infection of resting CD4 T cells

*pre-integration latency- short term HIV reservoir

*impaired reverse transcription results in accumulation of incomplete viral cDNA transcripts

*cDNA transcripts trigger an inflammatory form of cell suicide (pyroptosis)

  • Post-integration latency

*proviral DNA integrates into host chromosomes

*T cells differentiate into memory cells-long term HIV reservoir

29
Q

Viral Reservoirs

A
  • Short term reservoirs

*pre-integration latency in resting CD4 T cells

*extracellular virus particles trapped on follicular dendritic cells

*productive, persistent infection of monocyte-macrophage lineage cells

*latent infection of monocyte-macrophage lineage cells

  • Long term reservoir

*post-integration latency in memory CD4+ T cells

30
Q

Early stages of HIV infection

A
  • R5 viruses

*binds CCR-5 chemokine receptors

*responsible for majority of viral transmission

*nonsyncytia-inducing strains (NSI)

*macrophage tropic- previous designation

  • R5 viruses persist throughout the infection
  • Quasispecies appear after viremia peaks

*closely related viral genomes; have some variability

*result of point mutations within the viral genome

31
Q

Late stages of HIV infection

A
  • X4 viruses

*binds CXCR-4 chemokine receptors

*occurs in about 50% of patients

*syncytia-inducing strains (SI); more cytopathic

*involves acquiring point mutations in the env gene

  • Some viruses use both co-receptors (R5X4)

*occurs in later stage patients

32
Q

Course of HIV infection general overview chart

A
33
Q

Clinical Latency

A
  • Immune response limits the productive infection, but doesn’t eliminate it

*productive infection still occurs (lymph nodes)

*steady state viral load until T cells are depleted; viral set pint

  • Persistent, low level productive infection

*macrophages; dendritic cells etc.

  • Latent infection

*memory T cell

*possibly monocyte lineage cells including hematopoietic stem cells

*can reactivate => productive infection

  • Dont have AIDS at clinical latency; you are HIV+; you dont have AIDS until your immune system has been compromised to the point where you are developing opportunistic infections (<200 CD4 T cells in a mircoliter)

NOTE: clinical latency in an HIV+ individual is not the same as viral latency at the cellular level

34
Q

Acute Infection

A
  • Typically 2-4 wks after exposure
  • Mononucleosis-like syndrome

*T cell proliferation to try to clear virus

*viral levels in blood drop, but virus is not completely cleared

*virus persists in lymph nodes

*microglial cells in the CNS

  • Typically assoc. w/R5 virus
  • ~80% mucosal transmission- HIV infections are due to a single virus (founder virus)
  • HIV bind to dendritic cells; taken to lymph nodes

*binding mediated by DC-SIGN

*presented to CD4 T cells by dendritic cells

*HIV internalized by DCs; spread to CD4 T cells

  • Loss of CD4 T cells within mucosal-assoc. lymphoid tissue (especially GALT)

*extensive depletion of CD4+ CCR5+ memory T cells in GALT

+low % of CD4 T cells in GALT become productively infected and are directly killed by HIV-mediated cytolysis/apoptosis

+many resting CD4 T cells are killed indirectly by pyroptosis

+~80% of CD4 T cells in GALT are depleted in the 1st 3wks of HIV infection

*CD4 T cell counts return to ~normal levels in blood, but not in GALT

  • Virus incompletely cleared by the immune response- viral set point
35
Q

The importance of dendritic cells to the establishment of HIV infection

A
  • HIV stored in endocytic vesicles following entry via DC-SIGN; released via exocytosis
  • Productive infection of DCs; released via budding
  • HIV bound to DC-SIGN on surface of DC
  • Concentration of virions in the vicinity of CD4+ T cells
  • DCs present HIV peptides through MHC class II molecules to the TCR, resulting in T cell activation

*activates HIV gene transcription

36
Q

Loss of CD4 T cells

A
  • Highest rate of CD4 T cell death occurs during primary infection
  • HIV-induced cytolysis correlates w/CD4 levels on cells

*monocytes express less CD4 on their surface than T cells and are less easily killed (persisten, productive infection)

  • X4 viruses are more cytopathic than R5 viruses
  • Cell-mediated killing

*clears productively infected cells, not latently infected cells

37
Q

Stages of HIV infection Graph

A
38
Q

Immune response to HIV

A
39
Q

ARC vs AIDS

A
  • AIDS-related complex (ARC)

*lymphadenopathy, fever, weight loss, malaise

*opportunistic infections, diarrhea, fatigue

  • AIDS

*CD4 T cell counts <200/microliters; viral load >75,000 copies/ml

*AIDS-defining illnesses

+HIV wasting syndrome

+Kaposi’s sarcoma

+opportunistic infections

+HIV-assoc. dementia (HAD)

CMBM Exam 4 (14 decks)

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