HIV Flashcards
1
Q
AIDS/HIV structure and function
A
- Immune dysregulation (deficiency and hyperactivation)
- Selective infection of CD4 cells (T cells and mono/macs)
- GP120 transmembrane glycoprotein for binding to CD4/co-receptor (CCR5 or CXCR4)
- GP120 surrounded by carbohydrate shield, which we make Abs against but they aren’t neutralizing
- p24 capsid containing reverse transcriptase (creation of cDNA), integrase (migration and integration of cDNA into host genome), and protease (required for cleavage of viral proteins after release and activation of new viruses)
- 3 genes that are all polycistronic: gag (structural proteins), pol (polymerase/integrase proteins), and env (surface envelope proteins)
2
Q
Variability btwn HIVs
A
- Not all HIVs are equal, there is variability in mutation rate and virulence
- Virus mutates much faster than the TCR can keep up with
3
Q
Host cell compliance
A
- HIV requires some host cell functions for survival
- Cell receptors that are required for host cell (CD4, CCR5, CXCR4)
- Biochemical pathways (such as ubiquitin)
- Transcription factor activation for protein synthesis
- Unique aspect of HIV: targets the only cells that can stop the virus (T cells/macs)
- Virus replication can remain quiescent for years until the cell is activated and transcription begins, resulting in the creation of viruses w/ in the cell
4
Q
Spread of HIV
A
- Release of cell-free virus
- Exosome-mediated transmission
- Cell-cell transfer (most efficient, more rapid, evasion of host defenses)
- Sexually-transmitted HIV employs CCR5 as co-receptor
5
Q
Life cycle (cell-free viral transmission)
A
- GP120 binds to CD4 then co-receptor (either CCR5 or CXCR4)
- Capsid enters the cell after membrane fusion, reverse transcriptase makes cDNA out of the viral RNA
- Integrase moves cDNA to nucleus and integrates it into host genome (into sites that are transcriptionally active)
- Host TFs will transcribe the viral DNA and make viral proteins out of the resultant RNA
- The viral RNA and proteins are packaged up into immature virions, which bud off the cell taking the membrane w/ them
- The virions then use protease to cleave the proteins inside the virus, thus activating the virus for another round of infection
6
Q
Cell-cell transfer of HIV
A
- Presentation of HIV in trans from uninfected dendritic cells to T cells
- Env-induced, actin dependent synapse formation btwn infected and uninfected cells
7
Q
HIV infection: acute phase
A
- Primary lytic targets of HIV are CCR5+ (activated) memory CD4 T cells (Th1 effectors)
- Most T cells in blood are not activated (CCR5-), but these are infected as well
- Within 14 days of acute infection 50% of all T cells are gone
- Most of these are GI mucosa associated
- Initially there is a large spike in HIV viruses in blood (congruent w/ sudden drop in T cell count), but then the virus level falls and remains steady for years (usually)
8
Q
HIV infection: chronic phase
A
- 10 billion viruses are produced (and most destroyed) daily
- 1 billion CD4 T cells destroyed (and most replaced) daily
- W/ single drug Rx the WT virus is replaced by drug-resistant virus after 14 days
- Most virus-infected T cells are destroyed quickly (2 days), but resting CD4 central memory T cells can be infected and they take decades to eliminate (major reservoir for virus)
- Therefore we cannot get rid of the chronic infection due to resting central memory CD4 T cells
9
Q
Retroviral restriction factors
A
- There is a difference in susceptibility to retroviruses even when using similar receptors and co-receptors
- Human gene products that inhibit retrovirus replication
- APOBEC3 family of nucleic acid editing nzs generate C->U in retroviral cDNA and induces fatal mutations
- However, HIV Vif binds to and inhibits APOBEC3
10
Q
HIV immune evasion
A
- Low spike (GP120) density on virion surface (about 30)
- Glycan shielding of critical epitopes (GP120)
- Env heterogeneity and glycosylation (different from virus to virus)
- Preferential infection of HIV-specific T cells
- Vif to inhibit APOBEC3
- Nef decreases CD4 expression, blocks apoptosis
- Vpr: suppresses 12 production form monos
- Vpu inhibits tethering and NKT cell activation
- Escape mutants (high mutation rate): CTL generation cannot keep up w/ mutation rate of HIV
- Virion expression of host complement regulatory proteins (stops complement from binding to membrane)
- Chronic infection exhausts T cells
- Monos and T cells archive the virus
11
Q
HIV-induced immune deficiency
A
- Rapid and early destruction of 50% of mucosal memory T cells (either by direct cytotoxicity or syncytia formation)
- Direct cytotoxicity: activation of DNA-dependent protein kinase during integration
- Synctia formation: uninfected + infected T cells fuse to form large cell that is non-functional
- Decreased BM production of lymphoid precursors
- Decreased thymic output of new T cells
- Eventual destruction of lymph node architecture-> impaired clonal expansion
12
Q
Pathophysiology and pathogenesis of HIV
A
- Infection almost always occurs across mucosal barriers (using CCR5)
- Require CD8 T cells to eliminated virus infected cells
- CNS microglial (CD4 macrophages in brain) infection leads to neuro-encephalopathy
- Inappropriate/uncontrolled immune activation leads to proliferative disorders and systemic cytokine effects (sickness behavior)
- T cell deficiency and dysfunction lead to opportunistic infection (OI), the major cause of death
13
Q
Determinants of clinical manifestation
A
- Inoculum, route of exposure, invasiveness, virulence
- Cell/tissue tropism, immune avoidance and subversion
- Integrity of physical/anatomic barriers
- Prior immunization/exposure
- Immune responses
14
Q
Difficulty in HIV vaccination
A
- Immunologic correlates of protection are unknown
- Lack of animal studies
- Immune evasion factors impair use of broadly neutralizing Abs
- Neutralizing Abs arise in vivo only after multiple rounds of B cell maturation
- What to use as immunogen
15
Q
HIV epidemiology
A
- 2/3 of all HIV in sub-sarahan Africa (22.5 million)
- 33 million people world wide w/ HIV/AIDS
- Infects mostly blacks, whites, latinos (in US), but blacks have 46% of all HIV cases while being only 12% of the US population
- Major sources of transmission: male-male sex, IV drug use, heterosexual sex
