HIV 2 lecture

Overview of HIV and the Immune System

• HIV Complexity: HIV has a complicated relationship with the immune system, causing profound immune suppression.

• Immune Response: Contrary to earlier beliefs, the immune system mounts a powerful response against HIV, but despite this, the virus survives and destroys the immune cells fighting it.

Key Immunological Events

• Decline of CD4 T Cells: A hallmark of HIV infection is the gradual decline in CD4 T cell numbers.

• Immune System Changes:

  • Disruption of lymph node architecture.

  • Influx of CD8 T cells.

  • Loss of germinal centers, affecting antibody production.

• Dendritic Cells:

  • HIV exploits dendritic cells to reach lymph nodes, enabling the virus to transfer to CD4 T cells instead of being destroyed.

  • Recognition of HIV involves the JM3 ganglioside on the virus.

CD4 T Cell Function and Loss

• Drop in Function: CD4 T cell function declines not just due to reduced numbers, but also to other unknown factors linked to HIV.

  • Example: Transplant recipients on immunosuppressive drugs maintain better CD4 T cell function despite lower counts.

• Loss of Antibody Responses: As infection progresses, the ability to generate antibody responses diminishes despite increased serum IgG levels.

• Generalized Immune Dysfunction: Increased autoantibodies and flare-ups of allergies, like eczema, may indicate HIV infection.

HIV Lifecycle and Immune Response

• Viremia: After infection, there is a rapid replication of HIV leading to high levels of the virus in the blood (viremia).

• Strong Immune Response:

  • CD8 cytotoxic T cells and strong antibody responses to HIV proteins (GP120 and p24) occur initially.

  • 99% of the initial viral load can be eliminated, but 100% clearance is never achieved.

• Latent Phase: The phase where the virus remains mostly inactive, yet studies show active viral replication persists.

• Prognostic Indicators: viremia levels are key in predicting disease progression; low levels correlate with slower progression to AIDS.

CD4 T Cell Destruction Mechanisms

• Direct Killing: HIV can directly kill infected CD4 T cells and induce immune-mediated killing through antibody binding and CD8 T cytotoxicity.

• Apoptosis vs. Pyroptosis:

  • Apoptosis: Traditional cell death in permissive CD4 T cells.

  • Pyroptosis: Occurs in non-permissive CD4 T cells, driven by inflammatory signals and caspase activation.

  • Causes a cycle of death attracting more CD4 T cells, exacerbating the situation.

Therapeutic Approaches

• Drug Targeting:

  • Exploration of caspase one inhibition to potentially mitigate pyroptosis.

  • Drugs like V765 show promise in restoring CD4 T cell survival.

• Highly Active Antiretroviral Therapy (HAART):

  • Combination therapy of nucleoside/nucleotide analogues, non-nucleoside analogues, and protease inhibitors.

  • Despite being life-saving, challenges such as drug resistance and side effects remain.

• Economic Barriers: Cost of treatment is an obstacle in resource-limited settings.

Vaccine Development Challenges

• Vaccine Types: Efforts focus on prophylactic (preventing infection) and therapeutic (boosting response in infected individuals) vaccines, but success has been limited.

• Immunological Issues:

  • High mutation rates of HIV challenge vaccine development.

  • Lack of suitable animal models (e.g., HIV does not affect chimpanzees much).

• Current Research Focus: Searching for conserved epitopes and successful antibodies from immune responders.

Microbicide Research

• Glycerol Monolaurate: Studied as a potential microbicide that blocks inflammatory processes and protects against acute HIV infection in animal models.

Conclusion

• Ongoing Challenge: Continued struggle against HIV despite advancements in ART, vaccinations, and treatment strategies. The high mutation rate of the virus complicates efforts to control its progression and elimination.