84: Genetics of HIV

Key Points

• Disease summary:

  • HIV is a blood-borne, sexually transmissible virus that causes immunodeficiency by infecting CD4+ helper T cells. The infection causes an inversion of the normal CD4/CD8 T-cell ratio, dysregulation of B-cell antibody production, and enhances susceptibility to opportunistic infections at advanced disease stages.

  • HIV is a lentivirus, part of the Retroviridae family, which is an enveloped, positive-sense RNA virus that replicates with a DNA intermediate called a provirus. The provirus integrates into the host-cell DNA and persists for the lifetime of the cell.

  • The disease is marked by three phases—acute HIV seroconversion, asymptomatic chronic HIV infection, and acquired immune deficiency syndrome (AIDS). Depending on the host genetics, the duration of each phase can vary. Acute seroconversion is marked by nonspecific symptoms including fever, flu-like illness, lymphadenopathy, and rash which may occur in half of all people infected with HIV. The asymptomatic infection may last for 5 to 10 years on average until the development of AIDS, which occurs when the CD4+ count falls below 200 cells/mm³. At this stage, individuals are at risk for opportunistic infections such as Pneumocystis pneumonia, esophageal candidiasis, mycobacterial disease, cryptococcal meningitis, cytomegalovirus (CMV) retinitis, and toxoplasmosis as well as malignancies such as lymphoma and Kaposi sarcoma.

  • For purposes of studying the susceptibility to HIV or AIDS, researchers have classified patients with atypical outcomes into four major categories: 1. exposed uninfected (EU) individuals who remain uninfected after repeated exposure to HIV; 2. rapid progressors (RP) with uncontrolled viremia who progress to a CD4 count below 350 within 3 years; 3. long-term nonprogressors (LTNP) who are infected, yet maintain stable CD4 count and low level viremia for more than a decade; and 4. elite controllers or suppressors (EC/ES) who can suppress viremia for a decade or longer. These classifications have provided some insights into how viral and host genetics contribute to variations in outcome.

• Differential diagnosis of symptomatic HIV:

  • Influenza, Epstein-Barr virus (EBV), and other viral syndromes, immunodeficiency such as severe combined immune deficiency (SCID), B-cell and T-cell deficiency

• Monogenic forms:

  • CCR5Δ32 was a mutation identified in 1996 that protected against HIV infection in homozygotes. The mechanism of action is that HIV gp120 binds to CD4 to gain entry into the cell using CCR5 as the chemokine receptor to which HIV binds. Strong evidence for this mutation in homozygotes and partially in heterozygotes has demonstrated delayed HIV disease progression.

• Family history:

  • Not available

• Twin studies:

  • In HIV-discordant monozygotic twins, a reduction of naïve T cells with skewing of T-cell repertoire has been noted in the HIV-infected cohort.

• Environmental factors:

  • A few small studies have demonstrated environmental factors potentiating HIV progression and its sequelae. While tobacco abuse has not been shown to accelerate HIV progression, it has been shown to worsen opportunistic infections, particularly pulmonary infections. Stress and depression have additionally been shown to be associated with faster rates of progression. Additionally certain viral infections such as herpes simplex virus (HSV) increase risk for HIV ...