ORIGINAL ARTICLE Gene expression profiling of gut mucosa and mesenteric lymph nodes in simian immunodeficiency virus-infected macaques with divergent disease course M.D. George, D. Verhoeven, Z. McBride & S. Dandekar Department of Medical Microbiology and Immunology, Davis Medical School, University of California, Davis, CA, USA Introduction Human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) infections lead to a pro- gressive loss of CD4 + T cells in peripheral blood and the development of immunodeficiency syndrome [6, 15, 16, 24, 28, 32]. Gut-associated lymphoid tissue (GALT) is an early target of the virus and a site of severe deple- tion of memory CD4 + T cell in primary HIV/SIV infection [7, 28, 30]. The disruption of T-cell homeosta- sis is also characterized by an increase in CD8 + T-cell percentages and local cytotoxic T cell (CTL) responses [1, 31, 33]. Enteropathologic changes associated with HIV or SIV infection have been well documented which include decreased nutrient digestive and absorp- tive functions, villous atrophy and disruption of mucos- al structure and function [9, 12, 17, 29, 35]. Molecular and immunological analysis showed that disease pro- gression in SIV and HIV infections has been correlated with ongoing viral replication, CD4 + T-cell depletion, high levels of immune activation and inflammation at mucosal sites and in lymphoid compartments [8, 11, 13, 18, 20]. These findings were supported by recent studies showing host gene expression profiles in GALT are pre- dominated by increases in lymphocyte activation and inflammation-associated transcription in both HIV and SIV infections [4, 5, 22]. Although pathologic changes in GALT during disease progression have been well investigated, our understanding about of the correlates of protection against HIV disease remains limited. The majority of HIV-infected patients progress to develop AIDS in the absence of anti-retroviral therapy, yet a small percentage are able to control viral replica- tion and disease progression in the absence of thera- Keywords digestion – expression profiling – inflammation Correspondence Satya Dandekar, Department of Medical Microbiology and Immunology, University of California, Davis, CA, USA. Tel.: (530)754 7313; fax: (530)754 7240; e-mail: sdandekar@ucdavis.edu Accepted May 2, 2006. Abstract Background Although the majority of drug-naı¨ve HIV-infected patients develop acquired immunodeficiency syndrome (AIDS), a small percentage remains asymptomatic without therapeutic intervention. Methods We have utilized the simian immunodeficiency virus (SIV)-infected rhesus macaque model to gain insights into the molecular mechanisms of long-term protection against simian AIDS. Results Chronically SIV-infected macaques with disease progression had high viral loads and CD4 + T-cell depletion in mucosal tissue and periph- eral blood. These animals displayed pathologic changes in gut-associated lymphoid tissue (GALT) and mesenteric lymph node that coincided with increased expression of genes associated with interferon induction, inflam- mation and immune activation. In contrast, the animal with long-term asymptomatic infection suppressed viral replication and maintained CD4 + T cells in both GALT and peripheral blood while decreasing expression of genes involved in inflammation and immune activation. Conclusions Our findings suggest that reduced immune activation and effective repair and regeneration of mucosal tissues correlate with long- term survival in SIV-infected macaques. J Med Primatol doi:10.1111/j.1600-0684.2006.00180.x J Med Primatol 35 (2006) 261–269 ª 2006 The Authors Journal compilation ª 2006 Blackwell Munksgaard 261