In the current grant period while studying Reiter's syndrome in HIV+ patients we encountered an entity often presenting as a rheumatic disease associated with a sicca syndrome that was designated diffuse infiltrative lymphocytosis syndrome, or DILS. The accumulated findings led to the view that genetic differences in the host immune recognition structures influence the course and outcome of HIV infection in those developing DILS towards a diminished tendency to develop impaired CD4 T-cell function and opportunistic infections through a massive lymphocytic response of CD8 T- cells and lesser proportions of CD4 T-cells. This response also appears to mediate the pathogenesis of the rheumatic disorder. These T-cell are characterized by a restriction in their alpha-betaTCR expression suggesting that there is an underlying common antigen recognition event in DILS. Because of the importance of the consequences of these recognition events to the general question of HIV infection, and particularly because DILS is a model for understanding the pathogenesis of idiopathic Sjogren's syndrome, the decision was made to focus this proposal on gaining a better understanding of the fundamental mechanisms underlying DILS.
The specific aims i nclude: development of an improved understanding of the natural history of adult and pediatric DILS. Characterization of HIV strain diversity in DILS at the functional and structural level. Obtaining an explanation for the preponderant localization of HIV in monocytes and why the evolution to T-tropic strains occurs at low frequency and then very late in the course of HIV infection in DILS. Delineation of genetic determinants of susceptibility to the development of DILS with emphasis on understanding the physico-chemical basis of the positive association with two structurally related MHC class II alleles, DRB1 *1102 and DRB1 *1301, and the conformationally determined pattern of strong positive and negative association with several class I alleles. Exploring the significance of the striking mimetic homology between the 3rd diversity region of the class II susceptibility alleles and a segment of the HIV-1 V3 loop involved in determining M-tropism that suggests individuals with DILS exhibit either tolerance of M-tropic strains, or more likely enhanced autologous reactivity against these strains through molecular mimicry which prevents evolution of HlV-1 to functional T-tropic strains. Initiation of a comprehensive analysis of the nature of the responding T- cell population and search for the antigenic determinant(s) driving this response using the over-utilized alpha-beta TCR elements as markers with the objective of understanding its significance in the outcome of the host-virus interactions.
