HIV/AIDS

HIV Biology: Virus and Replication Path

Human Immunodeficiency Virus

  • Human retrovirus with an outer glycoprotein coat, inner protein coat, and genetic material: RNA.

  • Types: HIV-1 and HIV-2.

  • Subtypes (clades): B, most common in North America and Europe.

  • Target cell: CD4+ T-lymphocyte.

Vocabulary

  • HIV – the virus

  • AIDS -- the disease

  • CD4+ -- the immune cells that HIV targets

  • PrEP – Pre-exposure prophylaxis

  • ARV – antiretroviral drugs

  • ART/HAART – highly active anti-retroviral therapy

  • ABC – abstinence, be faithful, use condoms

  • PEPFAR – President’s Emergency Plan for AIDS Relief

PEPFAR (“President's Emergency Plan for AIDS Relief”)

  • Established in 2003: Launched by U.S. President George W. Bush to combat the global HIV/AIDS epidemic, especially in sub-Saharan Africa.

  • Largest Global HIV/AIDS Program: The largest commitment by any nation to address a single disease, with over $100 billion invested.

  • Focus on Prevention and Treatment: Provides antiretroviral therapy (ART) to millions living with HIV, alongside preventive measures like education, condom distribution, and mother-to-child transmission prevention.

  • Impact: Saved millions of lives, reduced new infections and AIDS-related deaths, strengthened health systems, and built capacity for HIV care in many low- and middle-income countries.

Life Cycle of HIV

Key Steps of the HIV Life Cycle

  1. Penetration

  2. Reverse Transcriptase (RNA-DNA)

  3. Integration

  4. Transcription (DNA-RNA)

  5. Budding (new virions infect neighbor cells)

HIV Replication Cycle

  1. Fusion of the HIV cell to the host cell surface.

  2. HIV RNA, reverse transcriptase, integrase, and other viral proteins enter the host cell.

  3. Viral DNA is formed by reverse transcription.

  4. Viral DNA is transported across the nucleus and integrates into the host DNA.

  5. New viral RNA is used as genomic RNA and to make viral proteins.

  6. New viral RNA and proteins move to the cell surface, forming a new, immature HIV virus.

  7. The virus matures as protease releases individual HIV proteins.

HIV Evolves to Evade the Immune System

  • HIV replicates rapidly – several billion new viruses/day/infected person.

  • Ability to mutate and evolve makes HIV difficult to control.

  • Reverse transcriptase makes many random mistakes, resulting in new strains of HIV.

  • More virulent strains are typically found in late-stage infections.

  • Evolving quickly to evade the immune system is a major reason why HIV is so deadly.

HIV Devastates the Immune System

  • HIV destroys billions of CD4+ T cells daily, overwhelming the immune system's capacity to regenerate or fight infections.

  • Mechanisms of destruction include:

    • Killing cells directly

    • Apoptosis (cell suicide) combined with death of innocent bystander cells

    • Destruction of immune precursor cells

Where Can Drugs Act in the HIV Life Cycle?

  • Nucleosides contain only sugar + base.

  • Nucleotides contain sugar + base + phosphate group.

  • A nucleotide occurs before RNA and DNA, while a nucleoside occurs before the nucleotide.

Disease Progression: In the Absence of ART

  • Median time of progression from HIV infection to AIDS: 9-10 years.

  • Median survival time after developing AIDS: 9.2 months.

  • Clinical disease progression varies among individuals, ranging from two weeks to 20 years.

  • Statistics: 10 billion new virions created daily, 2 billion CD4+ cells destroyed daily (twice the rate of replacement).

Transmission Routes

  • Sexual transmission: Low efficiency (~1% per contact).

  • Injection drug use: High efficiency (~10% per contact).

  • Blood, blood products, tissue: Very high efficiency (~90% per transfusion).

  • Perinatal transmission: (~25% per birth).

  • Needlestick injury: (~1 in 300 exposures).

  • Breast Milk transmission: ??

HIV Social, Cultural, Political, and Economic Perspectives

Global Estimates

  • People living with HIV: 39.0 million.

  • New HIV infections: 1.3 million.

  • Deaths due to AIDS: 630,000.

  • Total infections since the start of the epidemic: 88.4 million, total AIDS-related deaths: 42.3 million.

What is UNAIDS?

  • UNAIDS stands for Joint United Nations Programme on HIV/AIDS.

  • Leads global efforts to end the HIV/AIDS epidemic by coordinating international action and supporting countries.

  • Goals:

    • Preventing new HIV infections

    • Ensuring universal access to HIV treatment and care

    • Promoting human rights and addressing inequalities

    • Advocating for policies and funding to support the global response to HIV/AIDS

Infections and Demographics

  • New HIV infections projected: 3600/day in 2024, with 50% in sub-Saharan Africa.

  • New infections among children under 15: 360/day.

  • New infections among adults (15+): 3200/day, with almost 46% among women.

  • Young people (15-24): about 30%, young women (15-24): about 18%.

  • Children with HIV: 1.5 million.

AIDS Related Deaths

  • AIDS-related deaths reduced by 69% since 2004 and 51% since 2010.

  • In 2023, around 630,000 died from AIDS-related illnesses worldwide.

  • Decline in mortality rates: 55% among women and girls, 47% among men and boys since 2010.

Women and Girls

  • Globally, 46% of new HIV infections among women and girls.

  • In sub-Saharan Africa: adolescent girls and young women account for over 62% of new infections.

  • In 2022, adolescent girls and young women aged 15-24 were 3x more likely to acquire HIV than male peers.

  • Weekly infections: 4000 adolescent girls and young women aged 15-24 in 2022, mostly in sub-Saharan Africa.

  • Dedicated HIV prevention programs for adolescent girls and young women: present in only 42% of high-incidence areas as of 2021.

Key Risk Factors for Women and Girls

  • Partner violence, access to care and resources, prostitution, and men having multiple partners/wives.

Key Socio-Cultural Factors Driving the Epidemic

  • Risk factors: ethnicity, poverty, gender relations, and geographic region.

  • Increasing incidence trends in the Middle East and North Africa, Eastern Europe, and Central Asia.

  • Key populations at risk include ethnic minorities, young women, injection drug users, and men who have sex with men.

Individual Risk Behavior Paradigm

  • Life experiences combined with personal choices lead to risk, modified by factors like substance abuse and mental health disorders.

Case Study of Male Circumcision for HIV Prevention

Overview

  • Objective: To investigate effectiveness of male circumcision in HIV protection in Africa.

Method and Setting

  • Randomized controlled intervention trial was conducted in South Africa.

Key Conclusion

  • Male circumcision offers 61% protection against HIV, preventing 6 out of 10 cases.

Guest Lecture

  • Evaluating health systems in the context of HIV

  • Identifying barriers to HIV care

  • Care continuums: sets of steps for people to progress toward care goals

  • HIV care: the Ryan White program funds care for about 50% of people living with HIV (PWH) in the US; primarily for those with low income.

ART

  • Evolution from many pills to one.

  • Reasons why people may not take their medicine: complex regimen, stigma, beliefs about medicine, cost, etc.

  • New medicine: Long-lasting injectable approved in 2021.

Intervention Barriers

Outer Setting

  • Limited transportation access, stigma, insurance issues, utility of funding from other payors.

Inner Setting

  • Barriers decrease motivation.

Individual Factors

  • Effective pills paired with unmet needs, lack of perceived need, eligibility issues, and substance use.

Interventions and Health Systems Perspective

Types of Interventions

  • Individual and community-level: risk awareness and prevention

  • Health facility-based: voluntary counseling, testing, drug treatment (including PrEP)

  • Human rights: police interventions, monitoring, and law reform

Goals of HIV Interventions

  • Prevent new infections, increase knowledge of serostatus, ARV access for people living with HIV, improve quality of life, and address human rights.

Three Intervention Types

  1. PrEP: behavioral and drug

  2. Human rights interventions

  3. Mother to child transmission prevention

PrEP Intervention

  • PrEP (Pre-exposure Prophylaxis): pill for people at risk of HIV.

  • Effectiveness: reduces risk from sex by ~99% when taken as prescribed, and about 74% for people who inject drugs.

  • Less effective when not taken as prescribed.

Targets (UN Goals)

  • 2014 UNAIDS goal: 90-90-90 (know status, link to ART, achieve viral suppression)

  • 2020 Fast Track Milestone: 95-95-95.

Human Rights Interventions

  • UNAIDS prioritized 7 human rights programs to include in AIDS responses:

    1. Reduce violence against women and increase women's resource control.

    2. Decrease HIV-related stigma and discrimination.

    3. Legal services for HIV-related issues.

    4. Monitoring and reforming laws and regulations.

    5. Rights and legal literacy programs.

    6. Sensitizing lawmakers and law enforcement.

    7. Training healthcare providers on human rights and medical ethics.

Mother to Child Transmission Interventions

  • Addressing prevention strategies for mother-to-child transmission of HIV.

What is Bias?

  • Any deviation from the truth or results due to systematic variations in measurement or study design flaws.

Key Features of Randomized Controlled Trials (RCTs)

  • Random allocation to intervention groups.

  • Identical treatment except for experimental treatment (placebo control).

  • Patients and trialists unaware until study completion.

  • Analysis focuses on estimating the size of differences in predefined outcomes.

Ethics and Equipoise

  • Equipoise: ethical prerequisite of RCT; no preference between treatments.