Mucosal Immune Dysfunction in AIDS Pathogenesis

The mucosal immune system plays a central role in both the transmission of HIV infection and thepathogenesis of AIDS. Most HIV infections are acquired through mucosal transmission, and quantitativeand qualitative defects of mucosal immunity are consistently present in all stages of pathogenicHIV and SIV infections. A series of recent studies has emphasized the role of a rapid, dramatic,and largely irreversible depletion of mucosa-associated lymphoid tissue-based memoryCD4+CCR5+ T-cells as a key determinant of disease progression in HIV-infected individuals andSIV-infected macaques. It has also been proposed that, in order to be effective, an AIDS vaccineshould prevent the early depletion of these mucosal CD4+ T-cells. However, the observation of depletionof mucosal CD4+ T-cells during the primary phase of nonpathogenic SIV infection of natural SIVhosts, such as sooty mangabeys and African green monkeys, suggests that additional pathogenicfactors are involved in the AIDS-associated mucosal immune dysfunction. These factors may include:(i) selective depletion of specific CD4+ T-cell subsets; (ii) dysfunction of other (non-CD4+) immunecells; and (iii) generalized immune activation. Importantly, the mucosal immune dysfunction observedduring pathogenic HIV and SIV infection is associated with translocation of microbial products (i.e.lipopolysaccharide) from the intestinal lumen to the systemic circulation where they may be responsible,at least in part, for the chronic immune activation that follows pathogenic HIV and SIV infections.The role of mucosal immunity in AIDS pathogenesis emphasizes the importance of understandingwhether and to what extent the HIV-associated depletion of mucosal CD4+ T-cells is reversible afterprolonged suppression of virus replication with antiretroviral therapy. Further studies of mucosalimmunity during primate lentiviral infections will be needed to better understand, and ultimatelyprevent and treat, the mechanisms underlying the AIDS-associated mucosal immune dysfunction.