Term
| What is the basic structure of the HIV virus? |
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Definition
1) 2 identical strains of RNA with associated enzymes that are enclosed in p24 capsid protein
2) Envelope is lipid bilayer with viral glycoproteins (trimeric complex with transmembrane gp41 (fusion) and external gp120 (binding)) |
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Term
| What different cells does the viral glycoprotein bind to? |
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Definition
1) gp120 binds CD4+ T cells, macrophages, and DCs
2) When gp120 binds binds CD4+ T cell, conformational change occurs where glycoprotein is more likely to bind chemokine co-receptors (CCR5 and CXCR4)
3) R5 viruses use CCR5 (T cells, macrophages and DCs) and X4 viruses use CXCR4 (T cells only) |
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Term
| How does chemokine co-receptor (i.e. CCR5 and CXCR4) binding affect viral entry? |
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Definition
| Binding exposes fusion domain of gp41, allowing viral membrane fusion and entry, where it is released in the cytoplasm and associated enzymes (RT, protease and integrase) are activated. |
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Term
| How does HIV integrate into the host immune system? |
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Definition
RT, Integrase and Protease
Reverse Transcriptase transcribes HIV RNA to a double stranded DNA ("proviral" DNA)
Integrase integrates proviral DNA into host DNA where it can be transcribed
Protease cleaves newly synthesized viral polypeptides into function viral protein components which are assembled in the cytoplasm to make new secretory viral particles |
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Term
| Where does most HIV transmission occur in the body? |
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Definition
1) 80% at mucosal surfaces (single virion is often enough)
2) transmitted virus traverses tissues layers and contacts Langerhans' cells and CD4+ T cells (matter of hours)
The most popular target is CCR5+CD4+ T-cells (80% of T cells).
3) 3-6 days after infection, virus spreads to LN (viral replication occurs here) and GALT, where it is passed to uninfected T-cells (ONCE IT REACHES THE LN, IT IS TOO LATE) |
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Term
| Where does viral replication take place? |
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Definition
Lymph Nodes leading to systemic dissemination
The LN is like a "buffet of activated T cells" |
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Term
| What do Th17 cells have to do with HIV infection? |
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Definition
| These are CD4+ T-cells that secrete IL-17 (mucosal immunity through PMN recruitment) that are preferentially depleted. Their depletion leads to CHRONIC INFECTION |
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Term
| How long does it take from transmission, to the time HIV-1 RNA is first detected in the plasma in the so-called "eclipse phase"? |
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Definition
Average of 10 days (7-21) (to eclipse period)
Early in infection, permanent reservoirs are already established in lymphoid organs |
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Term
| What is the body's primary immune response to HIV infection? |
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Definition
SHORT
1) PRRs lead to acute phase response (IL-1, IL-6, TNF-a) and cytokine storm from DCs and pDCs (IFN-a and IL-15)
2) Cytokines activate NKs and anti-HIV CD8+ T cell response occurs (CTLs partially control replication before escape)
LONG
1) PRRs in innate immune system recognize virus and acute phase reactants (IL-1, IL-6, TNF-a) appear in plasma.
2) Cytokine storm led by IFN-alpha and IL-15 from DCs and Plasmacytoid DCs leads to NK cell expansion, which release pro-inflammatory cytokines
3) Potent anti-HIV CD8+ T cell response is generated days before peak HIV viremia (10% of CTLs may be used!)
** Early Abs against envelope glycoprotein are directed at non-neutralizing sites!** |
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Term
| How does the HIV virus escape and persist, despite the huge anti-CD8+ T cell and innate responses? |
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Definition
Begins at peak of anti-HIV-specific CD8+ T cell response
Mutation Rate of RT, CD8+ cells get no help b/c CD4+ depleted, B cells are not making antibody and neutralizing Abs arrive too late (12 weeks).
1) High mutation rate due to error-prone RT. Best mutant persists and resists antibody attack.
2) Initial CD4+ T cell depletion and LN disruption means that CD8+ T cells are not getting help
3) LN damage in germinal centers (inflammatory) also affects B-cell development and antibody production
** By the time neutralization Abs arise around 12 weeks, the virus has altered its glycoproteins to prevent Ab binding ** |
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Term
| Why can't the extreme proliferation of NK cells take care of the acute infection arising from HIV? |
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Definition
They are dysfunctional with decreased cytotoxic function.
HIV causes decrease in MHC Class 1 expression, but these NK cells can't handle them! |
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Term
| What are some major characteristics of Chronic HIV infection? |
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Definition
Immunodeficiency through
1) HIV infection of CD4+ T cells causes loss (but can't explain total loss)
2) Th17 cell depletion in gut mucosa early in infection leads to gut "leakiness", which may allow gut microbial products to enter systemic circulation.
3) Bacterial release causes persistent immune activation of T cells, which makes them more available to virus for replication and depletion.
4) B-cell and T-cell exhaustion |
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Term
| What happens to pDCs in chronic HIV infection? |
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Definition
Leaky gut bacteria persistently stimulate TLR7, activating pDCs (inflammation damages LN)
pDC activation leads to IDO production and Treg differentiation (Tregs release IL-10/TGF-b to suppress immune response) |
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Term
| How do Tregs relate to HIV-specific immune responses? |
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Definition
Unclear! They both inhibit activated T cells (good) AND effector T cells (bad)
1) accumulation of Tregs in lymphoid tissues suppresses HIV-1 specific immune response
2) Decreased Th17:Treg ratio has been associated with sustained immune activation and disease progression |
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Term
| When does an HIV-infected individual have "AIDS"? |
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Definition
1) When CD4+ T cell count drops below 200 cells per mm3 or when person is diagnosed with AIDS indicator condition (along with HIV in blood)
2) Average time to AIDS is 8-10 years post-infection. Without treatment, they die in 2 years. |
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Term
| What are some clinical signs of AIDS? |
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Definition
1) Less virulent strains such as MAC can infect patients
2) Increeased systemic inflammation is present due to pro-inflammatory cytokines (TNF-a, for example, leads to cachexia)
3) Increased susceptibility viral-induced cancers such as B-cell lymphoma caused by EBV and Kaposi's sarcoma caused by HHV8
4) Dementia due to infection of macrophages in CNS (microglia) |
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Term
| What are some issues with HIV vaccine development |
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Definition
1) Viral mutation
2) HIV-1 genetic variation among strains
3) Immunogens have been unable to elicit broad neutralizing B responses
**gp120 Ab VRC01 is promising ** |
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Term
| How have immunotherapeutic strategies been used to treat HIV? |
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Definition
1) Cytokine-based therapies such as IL2, INF-a and IL-7 to boost immune response
2) Blockage of inhibitory receptors such as PD1 and CTLA-4
3) Vaccination geared towards HIV-specific boosting of immune response. |
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Term
| What happens to B-cells in HIV infection? |
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Definition
| Germinal centers in lymph nodes are destroyed (50% in 80 days) and B cells can't function properly |
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Term
| What does PD-1 and CTLA-4 have to do with HIV? |
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Definition
These are inhibitory receptors that lead to decreased T-cell function. They are up-regulated during the viral infection.
Some therapies focus on blocking these inhibitory receptors. |
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