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Human Immunodeficiency Virus & Acquired Immune Deficiency Syndrome (AIDS)

Human Immunodeficiency Virus (HIV) & Acquired Immune Deficiency Syndrome (AIDS)

Target Cells, Receptors, and Tropisms

  • Primary Targets for HIV-1 Infection

    • T-lymphocytes (T-cells)

    • Macrophages

  • 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 glycoprotein gp120 of HIV-1.

  • Co-receptors

    • Expressed on T cells and macrophages.

    • Bind distinct domains on gp120:

    • CXCR4 for T cells

    • CCR5 for macrophages

    • Determine tropism of HIV-1 strains.

    • Uncovers gp41 that induces fusion between the viral envelope and the plasma membrane.

Dendritic Cells

  • Role in HIV-1 Infection

    • Important targets during primary infection.

  • Characteristics

    • Antigen-presenting cells located in the blood and skin/genital tract (Langerhans cells).

    • Located in genital tracts, thus primary targets during sexual transmission.

    • Express CD4 and initially possess CCR5 co-receptor, maturing to express CXCR4.

HIV-1 Strains & Tropisms

  • Strain Classifications:

    • R5 Strains:

    • Use CCR5 co-receptor.

    • Tropism for macrophages and immature dendritic cells.

    • X4 Strains:

    • Use CXCR4 co-receptor.

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

    • R5X4 Strains:

    • Use either CCR5 or CXCR4.

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

    • All strains use the CD4 molecule as the primary receptor.

HIV Type in the USA

  • Predominant Type: B

Three Stages of HIV-1 Infection

  1. Primary infection

  2. Asymptomatic infection (latent period)

  3. Symptomatic disease progression (AIDS)

Primary HIV-1 Infection

  • Infection Process

    • R5 strains infect dendritic cells/macrophages at mucosal epithelium via CCR5.

    • Transports to lymph nodes and blood within 2 days, establishing viremia.

    • Explosive replication of virus occurs, with levels reaching 10^7 HIV-1/ml.

  • Symptoms

    • Approximately 80% develop flu-like symptoms (fever, headache, lymphadenopathy, night sweats).

    • Skin rash on the trunk, subsiding within 2 weeks; persistent lymphadenopathy and headache may linger.

  • Immune Response

    • Marked reduction of viremia due to HIV-1-specific immunity.

    • Provirus persists in HIV-1-infected macrophages as a reservoir.

Asymptomatic HIV-1 Infection (Latent Period)

  • ** duration**: Variable, measured in years; few clinical manifestations.

  • Virulence

    • Low levels of HIV-1 in peripheral blood.

    • Extensive replication of HIV-1 in lymph nodes leads to immune dysfunction and tissue destruction.

    • High mutation rates lead to numerous strains generating antigenic variation.

Antigenic Modulation

  • Mutation Rate

    • HIV-1 exhibits a mutation rate that is 5 times greater than influenza virus.

    • Daily mutations can range from 10,000 to 100,000.

  • Consequences

    • Leads to diverse HIV-1 strains showing varying virulence.

    • Emergence of X4 strains that target CD4+ T cells.

Symptomatic Disease Progression (AIDS)

  • Increased Virus Levels

    • Rising levels of HIV-1 in peripheral blood indicate a higher diversity of strains.

    • B-cell activation leads to hypergammaglobulinemia.

    • Shift from Th1 to Th2 cytokine production occurs.

CD4+ T-Cell Dynamics

  • Th1 and Th2 CD4+ T Cells

    • Th1 CD4+ T Cells: Stimulate cellular immunity.

    • Th2 CD4+ T Cells: Stimulate antibody production.

  • Consequences of Declining CD4+ T Cells:

    • Absolute numbers decline, resulting in immune deficiency.

    • Leads to anergic state and reduced T-cell functions.

    • Increased incidence of opportunistic infections.

CD4+ T-Cell Count Statistics

  • Normal Ranges:

    • Non-HIV individuals have 700 - 1000 CD4+ T cells/μl of blood.

    • HIV-infected are considered “normal” above 500 CD4+ T cells/μl.

  • AIDS Classification:

    • CD4+ T-cell count drops to < 200 cells/μl (CDC definition of AIDS).

Spectrum of Outcomes in HIV-1 Infection

  • Typical Progressors:

    • Develop AIDS 8 - 10 years after primary infection (75 - 80% of cases).

  • Rapid Progressors:

    • Develop AIDS in 2 - 3 years (about 10% of cases).

  • Nonprogressors (Long-term Nonprogressors):

    • Maintain health 15 - 30 years after infection (10 - 17% of cases).

Features of Nonprogressors

  • Lower viral load compared to progressors.

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

  • Normal lymph node architecture.

  • Attenuated strains of HIV-1 replicate poorly.

  • Possible genetic mutations in CCR5 confer resistance.

Symptomatic HIV-1 Disease

  • Early Clinical Signs:

    • Thrush, chronic herpes zoster, and genital herpes, with CD4+ T-cell counts > 200 cells/μl.

  • Severe Infections:

    • Pneumocystis carinii pneumonia, Toxoplasma encephalitis, and cryptococcal meningitis occur when CD4+ T-cell counts < 200 cells/μl.

  • When CD4+ T-cell counts < 50 cells/μl, mycobacterium avium complex, CMV disease, PML, and lymphoma may manifest.

Cutaneous Manifestations

  • Chronic recurrent herpes simplex virus lesions.

  • Progressive recurrent varicella-zoster virus lesions (shingles).

  • Anogenital warts due to uncontrolled HPV replication.

  • Kaposi’s Sarcoma:

    • Complex tumor characterized by spindle-shaped cell proliferation, leading to purple skin masses, and may spread to organs; primarily associated with HIV/AIDS and caused by human herpesvirus 8 (HHV-8).

Respiratory Complications

  • Pneumocystis carinii pneumonia (PCP): Most common pulmonary infection (60 - 80%).

  • Mycobacterium tuberculosis: Exhibits atypical patterns, becomes antibiotic-resistant, and shows negative PPD skin tests (anergic).

Ophthalmologic Abnormalities

  • Most common retinal disorders include microangiopathic changes (cotton wool spots) found in over 50% of patients.

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

Pediatric Manifestations of HIV-1 Infection

  • Vertical Transmission: 12 - 50% (average 25%) of children born to HIV-1-infected mothers are infected.

  • Accelerated Course: HIV-1 progression is faster in children, with 30% exhibiting CNS abnormalities.

  • Common opportunistic infections are prevalent in pediatric cases.

HIV-Associated Dementia (HAD)

  • Known as AIDS-dementia complex or HIV encephalopathy.

  • Infection Timeline: HIV-1 can be detected in cerebrospinal fluid within 2 weeks of primary infection, presenting with flu-like symptoms, headaches, and photophobia.

Clinical Presentation of HAD

  • Approximately 20% of AIDS patients may develop dementia before death, with an abrupt clinical course.

  • Initial Symptoms: Forgetfulness and loss of concentration, leading to behavioral changes like apathy and irritability.

  • Disease Progression: Leads to loss of motor control, gait unsteadiness, and tremors, eventually resulting in cognitive dysfunction, mutism, spasticity, with death occurring 3 to 6 months post-onset.

Neuropathology of HAD

  • Autopsy findings show signs of tissue wasting, indicated by below-average brain weight and significant enlargement of sulci, fissures, and ventricles.

Management of HIV-1 Infection (Antiviral Chemotherapy)

  • Goals:

    • Slow or prevent HIV-1 replication, mitigating immunosuppression.

    • Stop clinical manifestations caused by opportunistic infections and direct HIV-1 infection effects.

Antiretroviral Drugs

  • Stages of the Virus Life Cycle Targeted:

    1. Attachment

    2. Entry

    3. Uncoating

    4. Viral Gene Expression

    5. Genome Replication

    6. Assembly

    7. Maturation

    8. Release

Targets for Antiviral Drugs

  • Advantages of early or late-step inhibitors:

    • Target attachment, adsorption (entry), and release without needing intracellular activity.

  • Enzymatic Steps:

    • Focus on steps involving enzymes such as genome replication, assembly, and maturation which are low-concentration and well-understood targets.

Four Distinct Targets During HIV-1 Replication

  • Targets for Antiviral Therapy:

    1. Provirus DNA formation (reverse transcriptase)

    2. Nucleocapsid formation (assembly)

    3. Integration of provirus DNA into host DNA (integrase)

    4. Maturation of virion (protease)

Reverse Transcriptase Inhibitors

  • Nucleoside Reverse Transcriptase Inhibitors (NRTIs):

    • Azidothymidine (AZT) [Zidovudine, Retrovir] was the first FDA-approved drug that showed clinical benefit for HIV-1 management.

    • Benefits: Increased CD4+ T-cell counts, reduced opportunistic infections, and extended survival time.

    • Demonstrated proof-of-concept for the efficacy of antiretroviral drugs.

AZT Mechanism of Action

  • Details (6 points to memorize):

    1. A nucleoside analogue with an altered structure.

    2. Contains a thymidine base attached to ribose, with the normal 3’ OH replaced by an azido (N3) group.

    3. Leads to premature chain termination upon incorporation into a growing DNA strand.

    4. Preferentially blocks HIV reverse transcriptase.

AZT & Maternal-Infant HIV-1 Transmission

  • Well-tolerated in pregnancy with no adverse maternal effects.

  • Reduces transmission risk from 25% to 8% (60% to 70% reduction).

NRTIs Toxicities

  • Bone marrow toxicity leading to severe anemia/neutropenia.

  • Peripheral neuropathy (pain and numbness).

  • Pancreatitis.

  • Hepatic abnormalities (hepatitis).

  • Generalized clinical symptoms: fever, rash, nausea.

Protease Inhibitors

  • Mechanism:

    • Prevent cleavage of gag and pol polypeptide precursors, halting replication.

  • Clinical Efficacy:

    • Reduces viral load, increases CD4+ T-cell counts, lowers opportunistic infections, and extends survival.

Ritonavir (Norvir)

  • A peptidomimetic protease inhibitor used to manage HIV-1.

  • Mechanism of Action:

    • Binds to HIV-1 protease as a substrate but is not cleaved, remaining bound.

    • Two mechanisms:

    • Prevents gag polyprotein cleavage, resulting in immature virus particles.

    • Prevents pol polyprotein cleavage, inhibiting reverse transcriptase availability for replication.

Protease Inhibitors Toxicities

  • Common Toxicities:

    • Lipodystrophy: fat redistribution from face/limbs to the abdomen.

    • Concerns regarding long-term cardiovascular effects due to lipid metabolism disruption.

Combination Antiretroviral Therapy (ART)

  • First line of treatment: Highly Active Antiretroviral Therapy (HAART).

  • Treatment Regimen:

    • Combination of at least one protease inhibitor with two NRTIs (or other antiretroviral drugs).

  • Clinical Outcomes:

    • Significantly reduces HIV-1 load, improves immune functions, and prevents opportunistic infections, transforming AIDS into a chronic condition.

Integrase Inhibitors

  • Development phase lasted ~12 years due to challenges in crystallization.

  • Four integrase inhibitors available, providing effective viral suppression when used in combination with other HIV-1 medications.

  • Potentially beneficial for those with HAART/ART resistance.

Pre-exposure Prophylaxis (PrEP)

  • Combination of antiretroviral medications designed to prevent HIV-1 infection.

  • Reduces transmission risk by ~99%.

  • Available formulations include two antiretrovirals (NRTIs alone or with integrase inhibitor): Truvada, Descovy, Dovato, Biktarvy.

Premature Aging in HIV-1 Patients

  • Individuals with chronic infections show accelerated aging, exhibiting age-related disorders such as:

    • Cardiovascular disease

    • Cognitive impairment

    • Type II diabetes

    • Osteoporosis

    • Age-related macular degeneration

  • Estimated accelerated aging effect of up to 15 years.

Major Obstacles in HIV-1 Management

  • Direct attack and destruction of immune system components by HIV-1.

  • Establishment of latent/persistent infections via provirus DNA.

  • HIV-1 crossing the blood-brain barrier to infect the brain.

  • High mutation rate producing numerous antigenic variants complicates vaccine development, raising questions about strain/subtype inclusion in vaccines.

Conclusion

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