Hiv

AIDS - Biochemistry of the Virus, Spread, Detection, Drug Treatment

Biochemistry of HIV Virus

Structure of HIV

• Diameter: Approximately 100 nm.

• Envelope: Made of lipids, which embeds two transmembrane glycoproteins:

  • gp41: Trimeric glycoprotein that aids in the entry of the virus into host cells.

  • gp120: Surface glycoprotein that attaches to host cells.

• Encoding: Both gp41 and gp120 are encoded by the env gene of the virus's RNA genome.

• Core Proteins:

  • p6, p24: Core proteins that play structural roles within the virus.

  • p17: Matrix protein that supports the viral structure.

  • p7: Nucleocapsid protein involved in packaging the RNA genome and proteins.

  • All core proteins are encoded by the viral gag gene.

Viral Genome and Enzymes

• Viral RNA Genome: Contains two copies of approximately 10 kilobases (kb) of positive-sense RNA.

• Core Enzymes:

  • Integrase, Protease, Reverse Transcriptase: Critical enzymes for viral replication, encoded by the pol gene of the virus.

• Additional Proteins: Various other proteins coded by HIV-1 and HIV-2 perform immuno-modulatory or regulatory functions:

  • vpr (viral protein R): Involved in viral replication.

  • vif (viral infectivity protein): Enhances the infectivity of the virus.

  • nef (negative regulatory factor): Down-regulates CD4 and MHC class I proteins.

  • rev (regulator of viral protein expression): Facilitates the export of viral RNA from the nucleus.

  • tat (transactivator of transcription): Enhances transcription of viral RNA.

HIV Target Cells

• Targets:

  • Human immune system cells, particularly:

  • Helper T Cells (CD4+ T cells): Primary host cells for HIV.

  • Dendritic Cells: Play a role in antigen processing and presentation.

  • Macrophages: Act as immune effector cells.

• Consequences of Infection: Decline in CD4+ T cells leads to loss of cell-mediated immunity, increasing vulnerability to opportunistic infections and ultimately resulting in AIDS.

Differences Between HIV-1 and HIV-2

General Overview

• Genetic Distinction: HIV-1 and HIV-2 are both retroviruses; however, they differ genetically and behave differently within the host.

  • A study from 2008 indicated only 55% sequence identity between HIV-1 and HIV-2 genomes.

Progression and Impact

• Progression:

  • HIV-2 progresses more slowly than HIV-1 and is less fatal, with patients potentially having a longer asymptomatic period.

  • Review from 2011 noted a slower progression to AIDS with HIV-2 (
    lower mortality rates compared to HIV-1).

• Treatment: There is no cure available; however, effective treatments allow people with HIV to live long, healthy lives.

Characteristics of HIV-1 and HIV-2

• HIV-1:

  • Most common type (95% of all infections).

  • Highly contagious and originates in chimpanzees.

• HIV-2:

  • Less common, mostly found in West Africa.

  • Less infectious and has a slower progression rate.

  • Originates from the Sooty mangabey monkey.

Spread of HIV

Transmission Routes

• Main Methods: Four primary modes of HIV transmission include:

  • Sexual Intercourse: Most common.

  • Contaminated Syringes and Needles: Including piercing instruments.

  • Contaminated Blood and Products: Involves organs and tissues.

  • Mother to Child Transmission (MTCT): During birth or breastfeeding.

Infection Cycle

• Entry and Attack: Upon entering the body, HIV targets the immune system by seeking out CD4 cells, into which it enters and replicates, subsequently killing these cells.

• Immune Response: The immune system attempts to counteract the virus by creating more CD4 cells, but if production cannot keep pace, the CD4 count drops, leading to sickness.

Stages of HIV Infection Cycle

1. Entry and Binding:

   • HIV locates and binds to CD4 cells, attaching to receptors and releasing viral RNA and enzymes inside the cell.

2. Reverse Transcription:

   • Converts single-stranded viral RNA to double-stranded DNA with the help of reverse transcriptase.

3. Integration:

   • Newly formed viral DNA is integrated into the host cell nucleus using integrase, taking over the host cell's machinery.

4. Replication:

   • CD4 cells begin to create new copies of the virus, often resulting in mutations.

5. Budding and Maturation:

   • New virions mature and exit the host cells to infect others.

   • Protease enzyme aids in converting immature virions to mature, infectious ones.

Disease Progression

• Clinical Effects: Similarities in the progression of HIV-1 and HIV-2 towards AIDS; however, HIV-2 progresses less quickly due to its lower transmissibility.

• Viral Load and Immune Response:

  • HIV-2 infections typically present with lower viral loads (around 10,000 copies/mL) compared to millions in HIV-1. The body's immune response in HIV-2 may provide protective benefits, suggesting potential strategies to delay progression in HIV-1 patients.

Detection of HIV

• Testing Accuracy: While HIV tests are accurate, there is a window period post-infection where detection may not be possible. The timing of HIV detection is dependent on the type of test.

Types of HIV Tests

1. Antibody Tests:

   • Detect antibodies to HIV in blood or oral fluid.

   • Can take 23 to 90 days to detect HIV after exposure.

   • Rapid tests are only FDA-approved self-tests and usually show earlier detection when using blood from a vein.

2. Antigen/Antibody Tests:

   • Look for both antibodies and antigens (specifically, the p24 antigen that appears before antibodies).

   • Typically recommended in labs;

   • Detect HIV usually 18 to 45 days post-exposure from blood drawn from a vein; 18 to 90 days from a finger stick.

3. Nucleic Acid Tests (NAT):

   • Search for the virus in the blood, and are recommended for recent exposures or early symptoms.

   • Can usually detect HIV 10 to 33 days after exposure.

Drug Treatment

Overview of HAART (Highly Active Antiretroviral Therapy)

• Function: Inhibits viral replication and slows the destruction of CD4+ T cells.

• Composition: Consists of six main drug classes that target different stages of the viral lifecycle:

  • Goal of HAART:

  • Reduce morbidity and mortality, improve quality of life, decrease plasma viral load, prevent transmission, prevent drug resistance, and enhance immune function.

• Clinical Efficacy: With HAART, a reduction of HIV-1 RNA levels has been correlated with the near-zero risk of sexual transmission, even in condomless encounters. HAART is critical for preventing MTCT in pregnant patients as well.

Classifications of HAART Agents

1. Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTIs):

   • Require intracellular phosphorylation. These agents are nucleoside/nucleotide analogs with an absent hydroxyl at the 3’ end, resulting in premature DNA chain termination.

   • Examples: Abacavir, Didanosine, Lamivudine, Stavudine, Tenofovir, Zidovudine.

2. Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs):

   • Bind at a hydrophobic site on reverse transcriptase, causing conformational changes; inhibit nucleoside binding.

   • Examples: Delavirdine, Efavirenz, Nevirapine, Rilpivirine.

3. Protease Inhibitors (PIs):

   • Inhibit the proteolytic cleavage of gag/pol polyproteins, leading to the production of immature, non-infectious virions.

   • Examples: Atazanavir, Darunavir, Indinavir.

4. Integrase Strand Transfer Inhibitors (INSTIs):

   • Prevent integration of viral DNA into host chromosomes by binding to viral integrase.

   • Examples: Dolutegravir, Elvitegravir, Raltegravir.

5. Fusion Inhibitors (FIs):

   • Block viral fusion with CD4 T-cells through binding to gp41.

   • Example: Enfuvirtide.

6. Chemokine Receptor Antagonists (CCR5 Antagonists):

   • Prevent entry into CD4 T-cells by blocking interaction with the gp120 subunit.

   • Example: Maraviroc.