Persistence of Gut Mucosal Innate Immune Defenses by Enteric α-Defensin Expression in the Simian Immunodeficiency Virus Model of AIDS

Gastrointestinal mucosa is an early target of HIV and a site of viral replication and severe CD4(+) T cell depletion. However, effects of HIV infection on gut mucosal innate immune defense have not been fully investigated. Intestinal Paneth cell-derived alpha-defensins constitute an integral part of the gut mucosal innate defense against microbial pathogens. Using the Sly-infected rhesus macaque model of AIDS, we examined the level of expression of rhesus enteric a-defensins (REDs) in the jejunal mucosa of rhesus macaques during all stages of SIV infection using real-time PCR, in situ hybridization, and immunohistochemistry. An increased expression of RED mRNAs was found in PC at the base of the crypts in jejunum at all stages of SIV infection as compared with uninfected controls. This increase correlated with active viral replication in gut-associated lymphoid tissue. Loss of RED protein accumulation in PC was seen in animals with simian AIDS. This was associated with the loss of secretory granules in PC, suggesting an increase in degranulation during advanced SIV disease. The a-defensin mediated innate mucosal immunity was maintained in PC throughout the course of SIV infection despite the mucosal CD4(+) T cell depletion. The loss of RED protein accumulation and secretion was associated with an increased incidence of opportunistic enteric infections and disease progression. Our findings suggest that local innate immune defense exerted by PC-derived defensins contributes to the protection of gut mucosa from opportunistic infections during the course of SIV infection. The Journal of Immunology, 2011, 186: 1589-1597.