While our study was not designed to investigate these effects, it suggests that therapy interruption may result in increased opportunistic infections as seen in untreated SIV infection resulting increased RED expression following increased degranulation. We found a loss of intestinal Paneth cell granules and detection of RED protein in SIV-infected animals with SAIDS which was accompanied by increased immunostaining in the lumen of jejunal tissues, Pik3r1 suggesting high levels of secretion of REDs into lumen (Fig. in Ned 19 animals with simian AIDS (SAIDS). This was associated with the loss of secretory granules in PC, suggesting an increase in degranulation during advanced SIV disease. The -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 Ned 19 protection of gut mucosa from opportunistic infections during the course of SIV infection. Keywords:HIV, SIV, defensin, GALT, innate == INTRODUCTION == Gastrointestinal (GI) complications, including diarrhea, weight loss, and enteric opportunistic infections occur frequently in therapy-nave HIV-infected patients (1-2). HIV infection causes severe CD4+ T-cell depletion in gut associated lymphoid tissue (GALT) early in infection, which contributes to impaired T-cell responses against pathogens at gut mucosal sites (3). Studies on HIV pathogenesis have been focused on the impairment of HIV-specific immune response and its role in the development of AIDS (4-5). However, innate immune defenses play a critical role in the protection of GALT against pathogens, and impairment of the innate immune system may accelerate disease progression. A better understanding of the mucosal innate defenses during HIV infection will provide insights into the mechanisms of HIV enteropathogenesis. The GI epithelium is an important source of innate immune response and provides a functional barrier against enteropathogenic bacteria, viruses, and parasites. Paneth cells (PC) located at the base of intestinal crypts are key players in the innate immune defense of the intestinal mucosa and express an array of host defense proteins and peptides, including -defensins (6). Human PC produce two known -defensins, human defensin-5 (HD-5), and HD-6; whereas, rhesus macaque PC express several highly diverse enteric -defensins (7) termed rhesus enteric defensins (REDs), of which six have been reported (8-9). The role of defensins has been well-established in determining the composition of the small bowel microbiota (10) and in protecting the intestinal crypt epithelium against colonization by microorganisms (11-12). Anti-HIV activity of various -, -, and Ned 19 -defensins have also been reported but their role in controlling HIV infection is unknown (13-14). The loss of -defensin during HIV infection may lead to overgrowth of enteric pathogens resulting in gastrointestinal dysfunction. The simian immunodeficiency virus (SIV)-infected rhesus macaque model is most suitable for the study of HIV-associated enteropathy (15). Rapid depletion of CD4+ T-cells in GALT correlates with active viral replication during primary SIV infection (16). Effects of the SIV infection on enteric innate immune responses in the SIV model have not been fully explored. We hypothesize that mucosal innate immune defenses, including -defensin expression and secretion, play an important role in protecting the host against intestinal microbial pathogens in SIV infection and may locally compensate for the loss of T-cell mediated immune responses. Therefore, we sought to determine -defensin (RED) expression during SIV infection by analyzing intestinal tissues from rhesus macaques at different stages of infection with and without antiretroviral therapy (ART). Our data showed that RED mRNA expression increased in response Ned 19 to SIV infection. SIV-infected animals treated with ART also maintained RED expression. A marked reduction in RED protein levels was observed in gut mucosa of animals with advanced SIV disease, coinciding Ned 19 with increased incidence of opportunistic infections. Our findings highlight the importance of -defensins in protection against mucosal pathogens despite severe CD4+T-cell depletion. == MATERIALS AND METHODS == == Rhesus macaques, SIV infection and therapy == Peripheral blood and intestinal tissue samples from 44 colony-bred rhesus monkeys (Macaca mulatta) were evaluated (17). Animals were housed in accordance with American Association for Accreditation of Laboratory Animal Care guidelines. Samples from 6 healthy, SIV-negative animals served as negative controls. Thirty eight animals were inoculated intravenously with.