Etiology

• Family: Retroviridae

• Genus: Lentivirus

• Species

  • HIV-1: most common species worldwide

  • HIV-2: restricted almost completely to West Africa

• pol gene codes for a polyprotein which consists of

  • Protease: cleavage of gag and gag-pol proteins during maturation of the virion

  • Reverse transcriptase: converts viral RNA to dsDNA

  • Integrase: helps insert the viral genes into the host genome

• gag gene codes for gag protein, which consists of

  • Matrix protein (p17 protein)

  • Nucleocapsids

  • Capsid proteins (p24 capsid protein)

• env gene codes for gp160 which gets cleaved into envelope glycoproteins

  • gp120: attaches to host CD4+ T-cells

  • gp41: assists in fusion and entry of the virus into the host cell

• tat gene (trans-activator of transcription) codes for tat protein which promotes viral transcription

• rev gene: codes for the rev protein, which regulates translocation of unspliced and incompletely spliced mRNAs

• Sexual: responsible for ∼ 80% of infections worldwide

  • Risk per sexual act

    • Risk for men who have sex with men (MSM): 0.5% for receptive partner

    • Risk for male-to-female sex

      • 0.1% for female partner

      • 0.05% for male partner

  • Modifying factors

    • Viral load: studies have shown that transmission is unlikely if viral load is < 400 copies/ml

    • Circumcision: reduced risk of infection for circumcised men

    • Co-infection: genital inflammation (e.g., as a result of co-infection with other pathogens such as HPV or genital herpes) increases local virus concentration and therefore risk of transmission

    • Genital mucosal damage: increases risk of transmission

• Needle sharing: 0.67% per exposure through needle-sharing contact

• Needlestick injuries: 0.36% per injury

• Infectious blood on mucous membranes: 0.1% per exposure

• Blood transfusions: 0.00005% risk per transfusion (1 in 2 million)

• During childbirth (∼ 5–15%)

• Through breastfeeding after birth (∼ 5–20%)

Natural history of HIV infection

• HIV enters the body (e.g., via mucosal lesions or via infection of mucosal/cutaneous immune cells.), then attaches to the CD4 receptor on host cells with its gp120 glycoprotein (binding)

  • Cells that have CD4 receptors: T lymphocytes

  1. Viral envelope fuses with host cell, capsid enters the cell.

     • For fusion, CD4 receptor and a coreceptor (CCR5 in macrophages, and CCR5 or CXCR4 in T-cells) must be present.

     • Viral entry into macrophages via CCR5 mainly occurs during the early stages of infection, while entry via CXCR4 occurs in later stages.

     • Individuals without CCR5 receptors appear to be resistant to HIV, those patients either have a homozygous CCR5 mutation (substantial resistance) or a heterozygous CCR5 mutation (slower course).

  2. A virion's RNA is transcribed into dsDNA by viral reverse transcriptase and then integrated into the host's DNA by viral integrase.

  3. Viral DNA is replicated and virions are assembled

• Progression to chronic immunodeficiency

  • HIV infects CD4+ lymphocytes

  • During the clinical latency phase, the virus mainly replicates inside the lymph nodes.

  • Increasing loss of CD4+ lymphocytes impairs immune function and, thereby, facilitates opportunistic infections and development of malignancies (AIDS).

• Because HIV infects cells of the immune system itself, activation of cellular immunity is a factor that paradoxically helps the virus spread and ensures chronic persistence of the infection.

• HIV evades immune control via:

  • Genetic mutation and recombination

  • Downregulation of MHC class I surface molecules in infected cells