This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Gastrointestinal (GI) syndromes, including chronic diarrhea and malabsorption, are frequent manifestations of HIV infection and often occur in the absence of identifiable opportunistic infections. These syndromes are generally not life threatening, although they are a major cause of morbidity and contribute to wasting seen in patients with AIDS. The exact mechanisms involved in the pathogenesis of HIV-associated GI syndromes are poorly understood, but they are likely due, at least in part, to HIV infection of the gastrointestinal tract. The GI tract contains the largest pool of immune cells in the body and is a major target organ for HIV and SIV replication [1]. As such, a great deal of emphasis has been placed on the potential role of immune cell destruction in the pathogenesis of this syndrome. However, we have recently observed histopathological changes in the enteric nervous system (ENS) of SIV-infected macaques with AIDS. This SIV-associated enteric neuropathy is characterized by increased numbers of activated, inflammatory macrophages within and immediately adjacent to the enteric ganglia with evidence of neuronal injury and degeneration. Based on these observations we put forward the concept that GI disease and wasting associated with HIV infection and AIDS are clinical manifestations of an inflammatory neuropathy of the ENS. Our hypothesis is that functional abnormalities of the GI tract caused by HIV/SIV infection result from changes in the structure and/or function of the enteric nervous system caused by the accumulation of inflammatory cells within the enteric neural microenvironment. These inflammatory cells secrete metabolites or cytokines that result in neurodegenerative changes and neuronal dysfunction that contribute to GI disease and wasting. To test our hypothesis we propose to utilize the SIV-infected rhesus macaque model of AIDS to address the following Specific Aims:
Aim 1 : Determine host factors responsible for the induction of enteric neuropathy and gastrointestinal disease by:
Aim 2 : Evaluate the impact of SIV-associated enteric europathy on the development of functional abnormalities of the intestinal absorptive epithelium. The primary goals of this project are to reveal new insights into the pathophysiology of AIDS enteropathy through studies of the enteric nervous system using the SIV-infected macaque model of HIV/AIDS. This will lead to a better understanding of the mechanisms involved in the induction of intestinal disease by HIV and SIV and will direct the design of novel treatment options targeted at modulating ENS inflammation and function.
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