(Taken directly from the application) Gastrointestinal syndromes, including diarrhea and wasting, are frequent manifestations of HIV infection and often occur in the absence of opportunistic infections. The pathogenesis of these syndromes is poorly understood but the intestinal tract is a major target organ for HIV infection. This is due, at least in part, to the fact that the intestinal tract contains the largest pool of immune cells in the body. Furthermore, we have recently demonstrated that intestinal lymphoid tissues are the primary sites of viral replication and CD4+ T cell depletion. The rapid and profound loss of CD4+ T cells must result in significant local immune dysfunction. We hypothesize that immune dysfunction caused by SIV/HIV infection disrupts the functional relationship between the gut epithelium and the mucosal immune system causing alterations in mucosal architecture and function that contribute to wasting and disease progression. To test our hypothesis we plan to: 1) Examine the role of viral determinants and route of infection on the development of intestinal CD4+ T cell depletion, GI disease, and wasting using molecular clones of SIV with varying cellular and tissue tropism. This will be achieved by infection of macaques with SIVmac239, which replicates poorly in macrophages; SIVmac239/316, a macrophage competent variant of SIVmac239; and SIVmac239/YEnef, an acutely enteropathogenic variant of SIVmac239 that differs by only two amino acids in the nef gene. 2) Determine host factors responsible for the induction of intestinal disease by: a) examining the immunophenotypic composition of the intestinal immune system and the expression of select endothelial and leukocyte adhesion molecules and chemokine receptors in the intestinal tract of SIV-infected animals over time, and b) investigating the functional significance of adhesion molecules and chemokines in AIDS enteropathy by blocking the function of relevant adhesion molecules (MAdCAM-1/alpha-4 beta-7) and chemokines (CXCR3/IP-10) in vivo in an attempt to ameliorate or prevent the disease. The ability to examine both host and viral determinants of disease from the clinical to the molecular level over time makes the macaque model of AIDS extremely valuable for defining the pathogenesis of AIDS-related intestinal dysfunction and developing novel therapeutic strategies.
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