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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE011348-03
Application #
2132612
Study Section
Special Emphasis Panel (ZDE1-YS (33))
Project Start
1994-09-30
Project End
1998-09-29
Budget Start
1996-09-30
Budget End
1998-09-29
Support Year
3
Fiscal Year
1996
Total Cost
Indirect Cost
Name
Weill Medical College of Cornell University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
201373169
City
New York
State
NY
Country
United States
Zip Code
10065
Dang, C T; Magid, M S; Weksler, B et al. (1999) Enhanced endothelial cell apoptosis in splenic tissues of patients with thrombotic thrombocytopenic purpura. Blood 93:1264-70
Mitra, D; Kim, J; MacLow, C et al. (1998) Role of caspases 1 and 3 and Bcl-2-related molecules in endothelial cell apoptosis associated with thrombotic microangiopathies. Am J Hematol 59:279-87
Crombie, R; Silverstein, R L; MacLow, C et al. (1998) Identification of a CD36-related thrombospondin 1-binding domain in HIV-1 envelope glycoprotein gp120: relationship to HIV-1-specific inhibitory factors in human saliva. J Exp Med 187:25-35
Mitra, D; Jaffe, E A; Weksler, B et al. (1997) Thrombotic thrombocytopenic purpura and sporadic hemolytic-uremic syndrome plasmas induce apoptosis in restricted lineages of human microvascular endothelial cells. Blood 89:1224-34
Lee, A W; Mitra, D; Laurence, J (1997) Interaction of pregnancy steroid hormones and zidovudine in inhibition of HIV type 1 replication in monocytoid and placental Hofbauer cells: implications for the prevention of maternal-fetal transmission of HIV. AIDS Res Hum Retroviruses 13:1235-42
Laurence, J; Mitra, D (1997) Apoptosis of microvascular endothelial cells in the pathophysiology of thrombotic thrombocytopenic purpura/sporadic hemolytic uremic syndrome. Semin Hematol 34:98-105
Mitra, D; Laurence, J (1997) Quantitative RT-PCR for human Fas (CD95) expression. Biotechniques 22:442-6
Laurence, J; Mitra, D; Steiner, M et al. (1996) Plasma from patients with idiopathic and human immunodeficiency virus-associated thrombotic thrombocytopenic purpura induces apoptosis in microvascular endothelial cells. Blood 87:3245-54
Laurence, J; Mitra, D; Steiner, M et al. (1996) Apoptotic depletion of CD4+ T cells in idiopathic CD4+ T lymphocytopenia. J Clin Invest 97:672-80
Mitra, D; Steiner, M; Lynch, D H et al. (1996) HIV-1 upregulates Fas ligand expression in CD4+ T cells in vitro and in vivo: association with Fas-mediated apoptosis and modulation by aurintricarboxylic acid. Immunology 87:581-5

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