HIV 2 ppt

Overview of HIV and Immunological Events

• Date of Presentation: December 1, World AIDS Day, by Prof. Bill Keevil.

HIV and the Immune System

• Complex Relationship: HIV interacts uniquely with the immune system, causing significant immunosuppression over time.

• Immune Response: Early on, the immune system responds vigorously to HIV, generating a powerful response that is typically effective against other viruses, but HIV's characteristics allow it to evade this response and persist.

Changes in the Immune System During HIV Infection

Key Changes

• CD4 T Cell Decrease: A hallmark of HIV infection is the gradual decline of CD4 T cell counts, indicating immunological disruption.

• Additional Immune Changes: Other immune alterations occur, including changes in lymph nodes and T cell functionality.

Lymph Node Changes During HIV Infection

Initial Phase

• Swollen Lymph Nodes: Common in HIV+ individuals during the initial infection phase.

• Histological Findings: • Disruption of lymph node architecture, • Influx of CD8 T cells, • Loss of germinal centers.

Dendritic Cell Role in HIV Infection

• Function of Dendritic Cells (DCs): Patrol tissues and present pathogen fragments to CD4 T cells, initiating immune responses.

• HIV Exploitation: HIV is taken up by DCs and transported to lymph nodes to evade destruction.

• Recognition Mechanism: The virus's GM3 ganglioside aids in its uptake by DCs, allowing it to circumvent immune detection.

CD4 T Cell Function and Loss

Loss of Function

• Over the course of infection, HIV+ individuals exhibit a decline in CD4 T cell function, not solely explained by cell count reductions.

• Transplant Comparison: Immunosuppressed transplant patients maintain better CD4 T cell function despite comparable cell loss.

Immune Response Dynamics

Early Immune Response

• Viraemia: Rapid viral replication leads to high blood virus levels.

• CD8 T Cell Response: Strong response against HIV proteins (gp120, p24) noted.

• Latency: The disease eventually enters a latent phase following the immune response.

Latent Stage Insights

• New methods reveal persistent active viral replication even during lew latency periods.

• Prognostic Indicator: Low viral RNA levels correlate with slower disease progression.

• Structural Abnormalities: Lymph node damage becomes more pronounced as the disease progresses.

Immune System's Challenges Against HIV

• HIV's Survival Tactics: High replication and mutation rates; hiding as a provirus; evasion of immune detection through rapid antigenic changes.

Mechanisms of CD4 T Cell Loss

Causes of Loss

• Direct HIV-induced cell death and immune-mediated destruction of infected CD4 cells.

• Soluble gp120 Presence: High levels in the blood contribute to CD4 T cell death through various mechanisms.

Killing Mechanisms Overview

• Direct Lysis: HIV can directly lyse CD4 T cells.

• Antibody-Dependent Mechanisms: Infected cells may be targeted by antibodies and other immune cells (e.g., NK cells).

• Cytotoxic Response: CD8 T cells target infected cells presenting viral antigens.

Cell Death Pathways

Types of Cell Death

• Apoptosis: A process seen in HIV-infected, permissive CD4 T cells following full infection.

• Pyroptosis: Mediated by caspase-1 in abortively infected CD4 T cells, leading to inflammatory responses and attracting more CD4 T cells.

HIV Treatment and Drug Development

Antiviral Drug Challenges

• High Mutational Rates: Complicate treatment and create resistance to drugs.

• Initial Drug Use: First introduced anti-HIV drug was zidovudine (AZT), but resistance developed quickly.

• Combination Therapy: Effective use of multiple drugs reduces resistance rates and saves lives with estimated 2.9 million lives saved through Anti-Retroviral Therapy (ART).

Drug Types

1. Nucleoside Reverse Transcriptase Inhibitors (NRTIs): Insert themselves into viral DNA, terminating synthesis.

2. Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs): Bind to reverse transcriptase, inhibiting its function without attaching to DNA.

3. Protease Inhibitors: Prevent cleavage of viral proteins, inhibiting replication.

Combination Chemotherapy Benefits and Challenges

• Clinical Effectiveness: Combination therapies improve patient outcomes and reduce viral loads but are associated with side effects.

• Logistical Issues: Compliance with complex regimens and high costs limit access to necessary treatments, especially in low-resource settings.

Vaccination Strategies Against HIV

Types of Vaccines

1. Prophylactic Vaccines: Aim to protect uninfected individuals from HIV infection.

2. Therapeutic Vaccines: Intended to enhance immune responses in already infected individuals.

Challenges in Vaccine Development

• Immunological Complexity: High mutation rates and diverse subtypes complicate design.

• Long Testing Durations: Chronic disease progression makes efficacy evaluation lengthy.

Summary of HIV Developments

• Overview: Initial identification of AIDS in 1981, strain isolation in 1983. HIV primarily infects CD4+ T cells, leading to immunosuppression.

• Epidemiology and Current Statistics: 30 million individuals infected; vaccination and treatment strategies remain ongoing challenges.

• Impact of Treatment: Although ART suppresses viral loads, it does not eliminate infection due to mechanisms like Vif targeting interferon responses.

• Future Directions: Together with therapeutics, innovative strategies like microbiocides and pyroptosis inhibitors may advance treatment protocols.