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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
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?
3
Dr. Riaz Muhammad
Notes: Advanced Immunology
Chapter# 5: Immune Response to HIV Infection
Date: 10th
November, 2019
Made by Amjad Khan Afridi
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.
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?

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Immune Response to HIV Infection

  • 1. 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
  • 2. 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?
  • 3. 3 Dr. Riaz Muhammad Notes: Advanced Immunology Chapter# 5: Immune Response to HIV Infection Date: 10th November, 2019 Made by Amjad Khan Afridi
  • 4. 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.
  • 5. 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?