PATHOGENESIS OF INTESTINAL DYSFUNCTION IN SIMIAN AIDS

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Intestinal dysfunction, a prominent feature of HIV-1 infection, can occur in early stages of infection in the absence of enteric pathogens and is associated with poor prognosis. The mechanisms of HIV-associated enteropathy are not fully known. We have established that SIV-infected rhesus macaques are an excellent animal model of AIDS to study pathogenic mechanisms of the enteropathy and nutrient malabsorption in HIV infection. The overall objective of this proposal is to determine phenotypic and functional alterations in absorptive epithelial cells and lymphoid subsets in SIV-infected small intestinal mucosa and elucidate their role in the development of enteropathy and disease progression in rhesus macaques. The SIV model provides us with a unique opportunity to obtain and analyze intestinal tissues from early stages of viral infection through the asymptomatic and symptomatic stages of disease. We will determine the mechanisms of SIV-associated epithelial cell injury in small intestinal mucosa in the early stages of SIV infection and the subsequent development of pathologic and functional changes, including nutrient malabsorption. We will examine immunophenotypic and functional alterations and immune dysregulation in intestinal lymphoid cell populations that are important in immune surveillance and integrity of epithelia. Changes in these populations will be associated with intestinal SIV infection, the development of epithelial cell abnormalities, clinical malabsorption and clinical course. Specific aim 1: To characterize the nature and onset of intestinal epithelial cell injury and crypt hyperplasia in small intestinal mucosa during the course of SIV infection and determine its role in the development of pathologic and functional alterations. We will test our hypothesis that crypt epithelial cell injury and/or apoptosis are early events in SIV infection which can result in a compensatory increase in epithelial cell proliferation leading to development of crypt hyperplasia and resulting in pathologic and functional changes in jejunum. Specific aim 2: To determine changes in phenotype and function (cytokine expression and cytotoxic activity) in lymphoid cells involved in immunosurveillance of intestinal epithelium and examine their role in the development of enteropathy and disease progression. We will test the hypothesis that immune dysregulation and functional abnormalities in intestinal lymphoid cells can occur early in SIV infection and may be a mechanism for the development of enteropathy and disease progression in the animals. The proposed study promises to provide important information on pathogenic mechanisms of SIV-associated enteropathy that will be valuable for the development of more effective management strategies for HIV-associated intestinal dysfunction.