The acquired immune deficiency syndrome (AIDS) is reaching epidemic proportions in the United States. The disease is caused by a retrovirus, commonly called HTLV-III/LAV, that is tropic and cytopathic for T lymphocytes. Infection with the AIDS virus is dependent upon the action of an RNA dependent DNA polymerase (reverse transcriptase). In contrast, the replication and repair of DNA in the target T lymphocyte is mediated primarily, if not exclusively, by DNA polymerase-alpha. This major enzymatic difference between virus and host is a logical candidate for the selective development of anti-viral agents. Indeed, several deoxynucleoside analogs have recently been described that apparently inhibit viral replication by this mechanism. Unfortunately, many deoxynucleosides are not phosphorylated efficiently by the resting T lymphocytes that are potential targets for HTLV-III/LAV infection. An ideal agent for the treatment of AIDS should accumulate in both non-dividing and proliferating T lymphocytes, as well as inhibit reverse transcriptase. Previous experiments in this laboratory have shown that deoxyadenosine, and related compounds, are selectively phosphorylated and """"""""trapped"""""""" by human T lymphocytes, compared to other cell types. The purpose of the present studies is to design and evaluate specific analogs of deoxyadenosine that are similarly taken up by T lymphocytes, that resist degradation by cellular enzymes, and that render the T cells resistant to infection by HTLV-III/LAV. Intially, the uptake and metabolism of each deoxynucleoside will be examined in cultured human CEM T lymphoblasts, in mutants deficient in individual purine metabolic enzymes, and in normal T cells. Subsequently, the capability of selected agents to inhibit the in vitro infection of wild type and enzyme deficient CEM T cells by HTLV-III/LAV will be assessed. Finally, the ability of the drugs to protect normal peripheral blood T cells from HTLV-III/LAV infection will be determined. The anti-viral studies will be performed in association with Dr. Douglas Richman at the San Diego Veterans Administration Medical Center, with whom the principal investigator has an established collaboration.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI024466-03
Application #
3137485
Study Section
(SSS)
Project Start
1987-08-01
Project End
1990-07-31
Budget Start
1989-08-01
Budget End
1990-07-31
Support Year
3
Fiscal Year
1989
Total Cost
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
City
San Diego
State
CA
Country
United States
Zip Code
92037
Nobori, T; Szinai, I; Amox, D et al. (1993) Methylthioadenosine phosphorylase deficiency in human non-small cell lung cancers. Cancer Res 53:1098-101
Nobori, T; Reynolds, L; Orvis, L et al. (1992) A polymerase chain reaction-based method for isolation of gene-specific sequences from the interferon-alpha gene cluster. Anal Biochem 205:42-6
Terai, C; Wasson, D B; Carrera, C J et al. (1991) Dependence of cell survival on DNA repair in human mononuclear phagocytes. J Immunol 147:4302-6
Kekow, J; Wachsman, W; McCutchan, J A et al. (1991) Transforming growth factor-beta and suppression of humoral immune responses in HIV infection. J Clin Invest 87:1010-6
Carson, D A; Carrera, C J; Wasson, D B et al. (1991) Deoxyadenosine-resistant human T lymphoblasts with elevated 5'-nucleotidase activity. Biochim Biophys Acta 1091:22-8
Nobori, T; Karras, J G; Della Ragione, F et al. (1991) Absence of methylthioadenosine phosphorylase in human gliomas. Cancer Res 51:3193-7
Nobori, T; Hexdall, L E; Carson, D A (1991) A polymorphic region defined by pCN2 (the 3' nontranslated region of N-ras) maps to chromosome 9cen-p12. Hum Genet 87:433-7
Lotz, M; Kekow, J; Carson, D A (1990) Transforming growth factor-beta and cellular immune responses in synovial fluids. J Immunol 144:4189-94
Wasson, D B; Yamanaka, H; Carson, D A (1989) Utilization of 2'-deoxynad for ADP-ribose transfer reactions. Adv Exp Med Biol 253B:213-8
Carson, D A; Haertle, T; Carrera, C J et al. (1989) 2-halo-2',3'-dideoxyadenosines: metabolically stable dideoxynucleosides with activity against the human immunodeficiency virus (HIV). Adv Exp Med Biol 253B:395-8

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