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 one of the largest pools of immune cells in the body. Gastrointestinal syndromes including diarrhea, malabsorption and wasting are frequent manifestations of HIV infection and often occur in the absence of opportunistic infections. The pathogenesis of these intestinal syndromes is not known but recently a nearly identical syndrome has been reported in macaques infected with the closely related simian immunodeficiency virus (SIV). Therefore, we propose using the SIV/macaque model of AIDS to examine the pathogenesis of HIV-related intestinal dysfunction and wasting. Furthermore, we have recently identified and acutely enteropathogenic molecular clone of SIVmac239 which will greatly facilitate these studies. Our hypothesis is that the diarrhea, malabsorption and wasting seen in HIV-infected humans and SIV-infected macaques (excluding opportunistic infections) is due to SIV or HIV infection of resident immune cells and resulting immune dysfunction. This disrupts the functional interrelationship between the gut epithelium and the mucosal immune system causing alterations in mucosal architecture and function. To test our hypothesis we propose the following specific aims: l) Examine the role of viral determinants in the development and severity of GI disease 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; derivatives of SIVmac239 with potentially gut-specific env sequences and; a recently described acutely enteropathogenic variant of SIVmac239 designated SIVmac239/YEnef that differs by only 2 amino acids in the nef gene. 2) Determine host factors responsible for the induction of GI disease by: a) examining the immunophenotypic composition of the intestinal immune system and the expression of endothelial and leukocyte adhesion molecules in the intestinal tract of SIV-infected animals over time and; b) investigate the clinical significance of adhesion proteins in AIDS enteropathy by blocking the function of relevant (MAdCAM-l, alpha4beta7) adhesion proteins 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.
Showing the most recent 10 out of 35 publications
