Abstract

The goals are (1) to define the natural history of HTLV-III infection (2) to identify cofactors that, together with HTLV-III, are necessary for the development of AIDS (3) to clarify the role of HTLV-III neutralizing antibody in the pathogenesis of AIDS (4) to elucidate factors important in the pathogenesis of Kaposi's sarcoma. A cohort of homosexual men already followed for two years will be monitored at three month intervals for virological and immunological factors related to AIDS. Quantitative HTLV-III virology and serology studies will be performed and correlated with clinical status and T lymphocyte function. HTLV-III antigen detection techniques will be evaluated together with moleuclar hybridization procedures for viral genome detection. Qualitative differences among viral isolates in different study groups (healthy, ARC, AIDS) will also be studied. We will evaluate interactions between HTLV-III and other viruses (CMV, EBV) in this study population by hybridization techniques. The role of HTLV-III in the pathogenesis of central nervous system manifestations of AIDS will be expolored by virologic and immunohistochemical techniques. Our group and others have described the presence of neutralizing antibodies in subjects infected with HTLV-III. Antigens involved in the neutralization process will be evaluated by blocking experiments, and strain variation among virus isolates in neutralization patterns will be studied. The pathogenetic role of virus neutralizing antibodies in immune modulation of HTLV-III will be analyzed in vitro and in vivo. The pathogenesis of Kaposi's sarcoma in AIDS is unclear. The roles of HTLV-III, CMV and other cofactors in the transformation of putative target cells (endothelial, Schwann, and dendritic cells) will be evaluated. Kaposi's sarcoma DNA will be evaluated for endogenous oncogene expression by transfection of NIH 3T3 cells. Transfectants will be studied for human repetitive sequenc;es, as well as both known oncogenes and viral genes.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA035020-04
Application #
3172774
Study Section
Virology Study Section (VR)
Project Start
1983-05-01
Project End
1991-04-30
Budget Start
1986-05-01
Budget End
1987-04-30
Support Year
4
Fiscal Year
1986
Total Cost
Indirect Cost

  Institution

Name
Massachusetts General Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02199

  Publications

Margalith, M; D'Aquila, R T; Manion, D J et al. (1995) HIV-1 DNA in fibroblast cultures infected with urine from HIV-seropositive cytomegalovirus (CMV) excretors. Arch Virol 140:927-35
Schooley, R T (1995) HIV-1-specific cytotoxic T-cell responses. AIDS 9 Suppl A:S113-6
Rusconi, S; Merrill, D P; Hirsch, M S (1994) Inhibition of human immunodeficiency virus type 1 replication in cytokine-stimulated monocytes/macrophages by combination therapy. J Infect Dis 170:1361-6
Mazzulli, T; Rusconi, S; Merrill, D P et al. (1994) Alternating versus continuous drug regimens in combination chemotherapy of human immunodeficiency virus type 1 infection in vitro. Antimicrob Agents Chemother 38:656-61
Mazzulli, T; Rubin, R H; Ferraro, M J et al. (1993) Cytomegalovirus antigenemia: clinical correlations in transplant recipients and in persons with AIDS. J Clin Microbiol 31:2824-7
Margalith, M; Medina, D J; Hsiung, G D et al. (1993) Interactions between HIV-1 and cytomegalovirus in human osteosarcoma cells carrying both viruses. AIDS Res Hum Retroviruses 9:519-27
Conway, B; Bechtel, L J; Adler, K A et al. (1992) Comparison of spot-blot and microtitre plate methods for the detection of HIV-1 PCR products. Mol Cell Probes 6:245-9
Johnson, V A; Merrill, D P; Chou, T C et al. (1992) Human immunodeficiency virus type 1 (HIV-1) inhibitory interactions between protease inhibitor Ro 31-8959 and zidovudine, 2',3'-dideoxycytidine, or recombinant interferon-alpha A against zidovudine-sensitive or -resistant HIV-1 in vitro. J Infect Dis 166:1143-6
Eron Jr, J J; Johnson, V A; Merrill, D P et al. (1992) Synergistic inhibition of replication of human immunodeficiency virus type 1, including that of a zidovudine-resistant isolate, by zidovudine and 2',3'-dideoxycytidine in vitro. Antimicrob Agents Chemother 36:1559-62
Johnson, V A; Merrill, D P; Videler, J A et al. (1991) Two-drug combinations of zidovudine, didanosine, and recombinant interferon-alpha A inhibit replication of zidovudine-resistant human immunodeficiency virus type 1 synergistically in vitro. J Infect Dis 164:646-55

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