The simian immunodeficiency virus, SIVmne, has a high degree of genetic homology to the human lentivirus HIV-2 and a lower but still quite significant homology to HIV-l, both of which are etiologic agents of human AIDS. SIVmne, like the other SIVs isolated recently causes a severe immunodeficiency in the nonhuman primate, Macaca nemestrina, which selectively involves CD4+ cells and is virtually identical to AIDS in man. We have found a linkage between the expression on a subset of CD4+ lymphocytes of adhesive receptors for high endothelial venules (HEV) and selective depletion and perhaps susceptibility to infection with SIVmne. This arose during our work to develop the macaque as a model system for analysis of the role such receptors have in directing organ- specific migration of lymphocytes through lymph nodes, Peyer's patches, and inflammatory sites. With the monoclonal antibodies (Mabs) Hermes-l and recently with Hutch-l we have defined two distinct types of CD4+ lymphocytes, HEV receptor/hi and lo, which differ markedly in response to mitogens, and capacity to recirculate through lymph nodes. HEV-receptor high cells are lost selectively in simian AIDS before the onset of clinical illness. Our future goals are a) to determine the mechanisms which underly the selective affects of SIVmne on these two cells, b) determine if Mabs to HEV receptors can be used as sensitive prognostic indicators in AIDS, and e) further define the role of HEV-receptors in directing lymphocyte migration and their structural features which confer organ-specific recognition of endothelial cells. We will also explore the capacity of interleukins to regulate expression of a) HEV-receptors on lymphocytes and b) their ligands on endothelium. We propose to examine linkage of these homing receptors to specialized lymphocyte functions and determine the in vivo migratory properties of normal lymphocyte subsets and T cell clones. Various aspects of the project use cellular immunology techniques as well as hybridoma technology and molecular biological methods such as subtractive hybridization cDNA cloning and in situ hybridization with SIV and interleukin specific probes.
