The hypothesis for this proposal is that salivary thrombospondins (TSP), either alone or in conjunction with other extracellular matrix glycoproteins, serve as a major source of the specific HIV suppressor activity found in human submandibular/sublingual salivas. This is based upon the restriction of TSP to high concentrations in submandibular saliva, its ability to block HIV-1 infection of appropriate target cells at levels found in salivas from both HIV negative and seropositive individuals, and its physicochemical properties, which mimic these reported for salivary HIV inhibitors. We will examine the immunobiology of TSP in terms of interactions with cell-free and cell-associated HIV-1, and with chronically infected cells. We will utilize a panel of viral isolates obtained from patients at various stages of HIV disease, so that inhibitory titers to autologous virus, rather than highly selected laboratory stains, can be examined and related to levels of TSP in paired saliva samples. Specificity will be sought utilizing assays for Epstein-Barr virus infection in vitro as well as assessment of growth characteristic of a human Kaposi's sarcoma cell line in the presence and absence of TSP and saliva, as KS is a prominent part of oral pathology together with persistent oral shedding of EBV, even in the presence of high-titer anti-HIV activity. Inhibitory mechanisms will be defined in terms of viral agglutination or aggregation, direct virion effects, alterations in target cells, and interactions with two other salivary components, fibronectin and MG1, reported to have some HIV inhibitory activity. Finally, based upon the observation that periodontal disease, prevalent in HIV infection, results in a gingival cytokine pattern--elevated IL-1 and IL-6, and depressed IL- 4--which favors upregulation of TSP, we will examine the possibility of further augmenting local TSP levels with growth factors which induce a similar cytokine pattern, including recombinant human growth hormone. It is hoped that this work will lead to definition of the role of TSP and other factors in salivary inhibition of HIV, its mechanism, an explanation for its variability in titer, its relationship to oral pathology in HIV disease, and the pharmacologic means by which it might be augmented.
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