Immune Response to HIV Infection

Immune Response to HIV Infection

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  1 Dr. Riaz Muhammad Notes:Advanced Immunology Chapter# 5: Immune Response to HIV Infection Date: 10th November, 2019 Made by Amjad Khan Afridi Immune Response to HIV Infection
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  2 Dr. Riaz Muhammad Notes:Advanced Immunology Chapter# 5: Immune Response to HIV Infection Date: 10th November, 2019 Made by Amjad Khan Afridi Immune Response to HIV • CD4: Helper T-cell responses • CTL: Cytotoxic T-cell responses • B-cell: Antibody responses • APC: Antigen Presenting Cells CD4 Responses To HIV • CD4+ T-cell responses to antigens are usually indirectly measured by proliferation (cell division). • Cytokine production is another measure of activation. HIV SPECIFIC CTL CTL responses are made to every HIV-1 protein: Gag, RT, Env, Pol, Nef, Vif, Vpr are more frequently targeted during chronic infection • Inverse correlation between viral load and levels of circulating HIV-specific CTL. • Emergence of CTL escape mutants over time. • Absence of detectable HIV-specific CTL, or oligoclonal CTL responses are associated with poor clinical outcome. CTL Responses To HIV CTL responses are measured by • 51Cr release assay (Killing) • ELISpot (Cytokine release) Antigen specific CD8+ T-cells can be quantified by tetramer staining. (Number of specific cells) CTL fail to eliminate HIV-1 Many chronically infected individuals have vigorous HIV-1-specific CTL responses yet, they almost always fail to adequately suppress the virus. Why? ➢ Epitope escape? ➢ CTL Exhaustion? ➢ Suboptimal CTL?
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  3 Dr. Riaz Muhammad Notes:Advanced Immunology Chapter# 5: Immune Response to HIV Infection Date: 10th November, 2019 Made by Amjad Khan Afridi
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  4 Dr. Riaz Muhammad Notes:Advanced Immunology Chapter# 5: Immune Response to HIV Infection Date: 10th November, 2019 Made by Amjad Khan Afridi Antibody Responses General Properties of Anti-viral Antibodies • Can be generated to any accessible portion of the virus. • Effective in blocking entry (neutralizing) if directed to viral receptors such as gp120 of HIV. • Can block fusion(neutralizing) if antibody (Ab) binds to fusion protein such as gp41 of HIV. • Can effect clearance of virus if it binds the virus and then binds Fc receptors on monocytes and macrophages. • Can also bind complement and kill enveloped viruses. • Most effective if they are present at the site of viral entry. Gp120 and Gp41-mediated fusion Neutralizing antibody responses to HIV are difficult to generate because: • Gp120 is presented as a trimer which protects some of the potential antibody binding sites. • Gp120 is highly glycosylated, meaning it has sugar molecules over much of its surface. Because many human proteins are glycosylated, humans rarely make antibody responses to glycoslyated portions of proteins.
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  5 Dr. Riaz Muhammad Notes:Advanced Immunology Chapter# 5: Immune Response to HIV Infection Date: 10th November, 2019 Made by Amjad Khan Afridi • CD4 binding site is devoid of glycosylation and relatively conserved between isolates but is masked by V1V2 loops and is in a depression which is too small for good antibody binding. HIV and APC’s • APC’s may exhibit altered: chemotaxis IL-1 production antigen presentation oxidative burst response antimycobacterial activity Antigen presenting cells can act as trojan horses Why does the immune response fail to clear HIV? • HIV integrates into the host genome. • Therefore, to eliminate HIV, infected cells must be killed. • Host factors can paradoxically enhance HIV replication. Therefore, by responding to HIV, CD4+ T-cells can be destroyed. • HIV can mutate and escape immune mediated opposition. • Suboptimal CTL responses can be elicited. • Sugar coating (glycosylation) and folding of gp120 protects against Ab recognition. • Critical binding sites on gp41 are revealed for only a short period of time. • APC’s may exhibit altered functions diminishing their ability to elicit immune responses. • Antigen presenting cells can act as trojan horses, spreading HIV to CD4+ T-cells as they begin to respond to antigen. Role of viral genes: Tat: Extracellular Tat stimulates CD4+ and CD8+ T-cells. Nef: Intracellular Nef appears to activate cells to promote viral replication. Affect on cellular function? Intracellular Nef downregulates CD4 and MHC class I molecules. In vivo significance?