Immunology and Infection: HIV and AIDS Overview

Objectives of the Lecture

• Understand the global scale of the HIV epidemic, including demographic trends and regional variations.

• Detail the complex structure of the HIV virus, infection strategies, and mechanisms of viral entry and replication.

• Connect the immune response to HIV with previous discussions on the immune system, highlighting how HIV evades immune detection.

• Describe the clinical trajectory leading to AIDS, including symptomatic stages and progression from HIV infection to AIDS diagnosis.

• Discuss the multifaceted challenges in developing an effective HIV vaccine, including the immune response required for protection and the virus's ability to mutate.

Global HIV Statistics 2022

• People Living with HIV: 39 million (range: 33.1-45.7 million)

• New Infections: 1.3 million (range: 1 million - 1.7 million), demonstrating ongoing transmission risks particularly among vulnerable populations.

• AIDS-related Deaths: 630,000 (range: 480,000 - 880,000), underscoring the importance of late diagnosis and treatment access.

• Accessing Antiretroviral Therapy (ART): 29.8 million, reflecting substantial global health efforts but highlighting disparities in access.

• Total Infections Since Epidemic Onset: 85.6 million (range: 64.8 million - 113 million) and the importance of historical context in understanding the epidemic's trajectory.

• Total AIDS-related Deaths Since Epidemic Onset: 40.4 million (range: 32.9 million - 51.3 million), emphasizing the need for ongoing public health strategies.

Breakdown of HIV Statistics by Demographic

Adults and Children Living with HIV (2022)

• Total living with HIV: 39 million

• Women (15+): 20 million, indicating a significant gender disparity in HIV prevalence.

• Men (15+): 17.4 million

• Children (0-14 years): 1.5 million, necessitating focus on prevention of mother-to-child transmission.

New Acquisitions of HIV

• Total: 1.3 million

• Women (15+): 540,000, with factors including socio-economic issues influencing infection rates.

• Men (15+): 640,000

• Children (0-14 years): 130,000

Deaths from HIV-related Causes

• Total deaths: 630,000, with a demographic breakdown showing distinct patterns in mortality, particularly in low-resource settings.

Historical Graphs of HIV Trends

• Trends in HIV Acquisition and AIDS-related Deaths (2010-2022): Historical data shows progress in reducing annual new infections and AIDS-related deaths, with statistical projections extending to the targets set for 2025 and 2030, which call for a more integrated response involving prevention, treatment, and care.

Understanding AIDS

Definition

• AIDS: A secondary immunodeficiency resulting specifically from the loss of immune function due to chronic pathogen exposure (HIV infection).

• Primary Immunodeficiency: Refers to genetic or developmental defects that lead to inherent immune dysfunction, distinct from acquired conditions.

HIV Structure and Life Cycle

Composition of HIV

• Components: Lipid Bilayer, Viral Envelope Glycoproteins (gp120, gp41), key proteins including reverse transcriptase, protease, integrase, matrix proteins, and capsid proteins.

• Genome Structure: Comprised of approximately 9kbp RNA genome with various genes, including gag (group-specific antigen), pol (polymerase), and env (envelope) critical for viral replication and function.

HIV Life Cycle

1. Binding: HIV gp120 binds to CD4 receptors and co-receptors (CXCR4 or CCR5), initiating infection.

2. Fusion: gp41 promotes the fusion of viral and host cell membranes to facilitate entry.

3. Entry: The nucleocapsid enters the host cell, bringing in RNA and essential viral enzymes.

4. Reverse Transcription: Viral RNA undergoes reverse transcription to DNA utilizing reverse transcriptase, crucial for genome integration.

5. Integration: The newly formed viral DNA integrates into the host genome, becoming proviral DNA.

6. Transcription and Translation: The host cell's machinery is hijacked to produce new viruses from the integrated proviral DNA.

7. Budding: New virions bud from the infected host cell, continuing the cycle of infection.

Immune Response to HIV Infection

• Acute Phase: High levels of HIV during initial infection lead to a significant drop in CD4+ T-cell counts, followed by a complex immune response characterized by the activation of both humoral and cellular immunity.

• Immune Mechanisms: Involvement of antibodies and cytotoxic T-lymphocytes (CTLs) in controlling the virus, while also identifying strategies employed by HIV to evade host immune responses.

Challenges in Immune Evasion

• HIV persists despite immune activation through various mechanisms: latent virus residing in reservoirs, high mutation rates complicating vaccine design, and the potential sequestration of the virus to evade immune detection.

Therapeutics and Vaccine Development

Antiretroviral Therapy (ART)

• Types of drugs: Targeting different aspects of HIV replication, including reverse transcriptase inhibitors, protease inhibitors, and integrase inhibitors, to manage infection and maintain viral suppression.

• Current approaches: Emphasize combination therapies to maximize efficacy and overcome resistance, addressing the need for continuous treatment adherence.

Vaccine Development Challenges

• Challenges: The rapid mutation rate of the virus complicates vaccine development, while limited animal models and concerns regarding safety of live-attenuated vaccines hinder progress. Past trials, such as those utilizing purified proteins (gp120) and recombinant adenoviruses, demonstrated insufficient protective efficacy, prompting re-evaluation of strategies.

Summary of Vaccine Considerations

• For an effective HIV vaccine, it is critical to mimic the immune response observed in individuals who are either cured or controlling their infection without treatment. However, challenges remain regarding stabilization of viral genomes and safe, ethical testing practices.

With ongoing research and evidence-building, strategies to combat HIV and its progression to AIDS continue to evolve against the backdrop of complex disease dynamics and public health challenges.