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.

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