D

Study Notes on HIV and AIDS

Human Immunodeficiency Virus & Acquired Immune Deficiency Syndrome (AIDS)

Overview of HIV and AIDS

  • HIV is the human immunodeficiency virus that leads to acquired immune deficiency syndrome (AIDS).

Target Cells, Receptors, and Tropisms

Primary Targets for HIV-1 Infection

  • T-lymphocytes (T-cells) and macrophages.

    • They are the primary targets for HIV-1 infection.

  • CD4 Molecule:

    • Expressed on the surface of T cells and macrophages.

    • Serves as the primary receptor for HIV-1.

    • Binds to distinct domains on the envelope gp120 molecule of HIV-1.

  • Co-receptors:

    • Expressed on T cells and macrophages.

    • Bind to distinct domains on gp120 (e.g., CXCR4 for T cells and CCR5 for macrophages).

    • Determines tropism of HIV-1 strains.

    • Exposure of gp41 which facilitates fusion between the viral envelope and the plasma membrane.

Dendritic Cells

  • Represent an important target during primary infection:

    • Act as antigen-presenting cells found in blood and skin/genital tract (e.g., Langerhans cells).

    • Crucial due to their location in genital tracts during sexual transmission of HIV-1.

    • Express CD4 molecule.

    • Initially express CCR5 co-receptor but can switch to CXCR4 co-receptor upon maturation.

HIV-1 Strains & Tropisms

Types of HIV-1 Strains

  • R5 Strains:

    • Utilize CCR5 chemokine receptor.

    • Tropism for macrophages and immature dendritic cells.

  • X4 Strains:

    • Utilize CXCR4 chemokine receptor.

    • Tropism for mature CD4+ T cells and dendritic cells.

  • R5X4 Strains:

    • Utilize either CCR5 or CXCR4 chemokine receptors.

    • Tropism for macrophages, dendritic cells, and CD4+ T cells.

  • All strains use CD4 molecule as the primary receptor.

Stages of HIV-1 Infection

Three Stages of HIV-1 Infection

  1. Primary infection

  2. Asymptomatic infection (“latent period”)

  3. Symptomatic disease progression (AIDS)

Primary HIV-1 Infection

  • Dynamics of Infection:

    • R5 strains infect dendritic cells/macrophages at the mucosal epithelium using CCR5 co-receptor.

    • Rapid travel to lymph nodes and bloodstream within 2 days, establishing viremia.

    • Explosive virus replication with counts up to 10^7 HIV-1/ml.

    • Common flu-like symptoms observed (~80% of individuals): fever, headache, lymphadenopathy, night sweats, and skin rash within 2 weeks. Persistent symptoms may continue.

    • Marked reduction of viremia due to immune response.

    • Persistence of HIV-1-infected macrophages serves as a reservoir (provirus).

Asymptomatic HIV-1 Infection (Latent Period)

  • Lasts variable duration, often measured in years with minimal clinical signs.

  • Viral Characteristics:

    • Low levels of HIV-1 detectable in peripheral blood.

    • Extensive replication in lymph nodes correlates with deteriorating immune functions and structural damage to lymph nodes.

    • High mutation rate leads to diverse HIV-1 strains.

Antigenic Modulation

  • Mutation Rate:

    • HIV-1 exhibits a mutation rate 5X greater than the influenza virus (10,000 to 100,000 mutations daily).

    • Generates numerous antigenically distinct strains.

    • Allows the emergence of X4 strains with tropism for CD4+ T cells.

Indications of Asymptomatic Period

  • Virus replication is managed by CD8+ T-cell immunity and influenced by a dominant Th1 cytokine profile.

  • Latent state in many resting CD4+ T cells.

  • Typical asymptomatic duration: 5-8 years.

  • Individuals are infectious and can transmit the virus, but gradual CD4+ T-cell loss is observable.

Symptomatic Disease Progression (AIDS)

  • Increasing HIV-1 levels in blood, diversity of strains also rises.

  • Predominance of X4 strains with CD4+ T cell tropism.

  • Chronic B cell activation leading to hypergammaglobulinemia.

  • Cytokine shift from Type 1 (Th1) to Type 2 (Th2).

Decline of Immune Functions

  • Absolute CD4+ T cells decrease leading to marked immune deficiency.

  • Delayed-type hypersensitivity T-cell functions decline leading to anergia.

  • Protections from CD8+ T-cells also diminish.

  • Onset of numerous opportunistic infections.

CD4+ T-cell Counts

  • Normal range: 700 - 1000 CD4+ T cells/μl peripheral blood.

  • Definition of AIDS by CDC: Classification occurs when CD4+ T-cell count drops below 200 cells/μl.

Spectrum of Outcomes

Outcome Classifications

  • Typical Progressors: Develop AIDS 8-10 years post-infection (75-80% of cases).

  • Rapid Progressors: Develop AIDS in 2-3 years (approximately 10% of cases).

  • Non-Progressors: Remain healthy for 15-30 years post infection (10-17% of cases, approximately 1 in 500).

Characteristics of Non-Progressors

  • Lower viral loads compared to progressors.

  • Strong immune response with broadly reactive neutralizing antibodies and potent CD8+ T-cell activity.

  • Normal lymph node architecture.

  • Poor replication of HIV-1 isolates in culture, potentially indicative of attenuated strains.

  • Exhibit mutations in genes for CCR5, leading to enhanced resistance against R5 strains.

Symptomatic HIV-1 Disease Manifestation

Initial Symptoms of Disease Progression

  • Early signs include chronic oral thrush, herpes zoster, and genital herpes; CD4+ T-cell counts remain > 200 cells/μl.

  • Severe conditions arise like Pneumocystis carinii pneumonia (PCP), Toxoplasma encephalitis, and cryptococcal meningitis at CD4+ counts < 200 cells/μl.

  • Conditions like Mycobacterium avium complex, CMV disease, progressive multifocal leukoencephalopathy (PML), and lymphoma appear at counts < 50 cells/μl.

Kaposi’s Sarcoma

Description

  • Rare skin tumor typically found in elderly non-HIV infected men from Eastern Europe; not associated with immune deficiency.

  • Characterized by spindle-shaped cell proliferation, yielding purple skin masses, possible internal organ dissemination.

  • Major opportunistic disease in HIV/AIDS patients, with human herpesvirus 8 (HHV-8) as the etiological agent.

Respiratory Complications of HIV/AIDS

  • Pneumocystis Carinii Pneumonia (PCP): Most common pulmonary infection in HIV/AIDS (60-80%).

  • Mycobacterium tuberculosis: Exhibits atypical patterns and increasing rates of antibiotic-resistant strains, often with normal chest X-ray and negative PPD skin test.

Ophthalmologic Abnormalities

  • Common retina disorders include microangiopathic changes (cotton wool spots) found in > 50% of patients.

  • Cytomegalovirus retinitis observed in ~40% of AIDS patients with CD4+ counts < 50 cells/μl.

Pediatric Considerations in HIV-1 Infection

Transmission and Progression

  • 12-50% (average 25%) of children born to infected mothers acquire HIV-1 through vertical transmission.

  • Course of infection in children is accelerated.

CNS Abnormalities and Infections

  • CNS abnormalities observed in 30% of infected children; opportunistic infections are common.

HIV-Associated Dementia (HAD)

Infection Timeline and Symptoms

  • HIV-1 can be detected in cerebrospinal fluid within 2 weeks post-infection.

  • Abrupt symptom onset in ~20% of AIDS patients leading to cognitive decline such as forgetfulness, apathy, and loss of motor control.

  • Average life expectancy post-dementia onset is 3-6 months.

  • Persistence of dementia occurs despite antiviral treatment.

Neuropathology

  • Autopsy reveals brain tissue wasting with lower than expected brain weight and enlarged sulci, fissures, and ventricles.

Management of HIV-1 Infection

Antiviral Chemotherapy Goals

  • Aim to slow or prevent HIV-1 replication and related immunosuppression, addressing associated clinical diseases from opportunistic infections or malignancies.

  • Intervention also addresses direct manifestations of HIV-1 infection (e.g., wasting disease, HIV-associated dementia).

Stages of Virus Life Cycle

  1. Attachment

  2. Entry

  3. Uncoating

  4. Viral Gene Expression

  5. Replication of Viral Genome

  6. Assembly

  7. Maturation

  8. Release
    (Reference: Fundamentals of Molecular Virology, N.H. Acheson, Ed, John Wiley & Sons)

Targets for Antiviral Drugs

Mechanism Considerations

  • Drug development focuses on early/late steps and enzymatic processes during replication, emphasizing enzyme inhibitors.

Primary Targets for Antiviral Therapy

  • Provirus DNA formation (reverse transcriptase).

  • Nucleocapsid formation (assembly).

  • Integration into host DNA (integrase).

  • Maturation of the virion (protease).

Antiretrovirus Classification

Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

  • AZT (Azidothymidine):

    • First FDA-approved drug (1987), temporarily increases CD4+ counts and reduces opportunistic infections, enhancing survival time.

    • Mechanism of Action:

      • AZT is a nucleoside analogue causing premature chain termination upon integration into the DNA molecule, preferentially blocking HIV reverse transcriptase.

    • Effectiveness in maternal-infant HIV-1 transmission reduction: from 25% to 8% (60-70% reduction).

    • Toxicities include bone marrow toxicity (anemia/neutropenia), peripheral neuropathy, pancreatitis, liver abnormalities, and generalized symptoms (fever, rash).

Protease Inhibitors (PIs)

  • Function to prevent cleavage of the Gag and Pol polyprotein precursors, essential for viral maturation, thus halting replication.

  • Efficacy demonstrated in reducing viral load, increasing CD4+ counts, and extending survival.

  • Ritonavir:

    • Peptidomimetic protease inhibitor developed through crystallization of HIV-1 protease.

    • Mechanisms: Prevents cleavage of both Gag (primary) and Pol (secondary action).

    • Toxicities: Lipodystrophy leading to fat redistribution, coronary disease risk with long-term use.

Combination Antiretroviral Therapy (ART)

  • Uses a protease inhibitor with two reverse transcriptase inhibitors, exhibiting additive/synergistic effects on reducing HIV-1 viral load and improving immunity.

  • Dramatic decrease in AIDS-related mortality with transformation of AIDS into a chronic disease; however, it has not led to a reduction in new HIV-1 cases.

Integrase Inhibitors

  • Approved after considerable development due to crystallization challenges, effectively suppressing the virus and minimizing resistance.

Pre-exposure Prophylaxis (PrEP)

  • Combination of antiretroviral drugs reducing the risk of HIV infection from sex by ~99%; includes various formulations (e.g., Truvada, Descovy).

Lenacapavir

  • A drug that binds to HIV-1 capsid protein, preventing virus assembly; effective in clinical trials showing a 99.9% success rate in preventing HIV-1 infection.

Accelerated Aging in HIV-1 Infected Individuals

  • Chronic HIV-1 infection leads to longer lifespans but also faster onset of age-related diseases: cardiovascular disease, cognitive impairment, type II diabetes, osteoporosis, and age-related macular degeneration.

  • Individuals experience accelerated aging by as much as 15 years.

Major Obstacles in HIV Treatment

  • HIV-1 directly targets and destroys immune system components, establishing latent infections via proviral DNA.

  • The virus can breach the blood-brain barrier, infecting the brain and showing high mutation rates leading to diversity in strains.

  • Challenges in vaccine development concerning which strains/types to include remain significant.

Conclusion

  • A safe and effective vaccine against HIV-1 infection has not yet been developed.