The long term objectives of this project are to clarify interactions among HIV-1, human leukocytes, and immune responsiveness, with the goal of utilizing this information to prevent the pathogenic consequences of infection, i.e. the development of AIDS.
The specific aims for this project period are to develop new strategies for the use of combination therapy for HIV-1 infection, determine the mechanisms for drug failure after prolonged therapy, describe the evolution of HIV-1 phenotypes and genotypes during various forms of therapy, and characterize the effects of antiviral treatments on HIV-1 specific cytotoxic T lymphocyte (CTL) reactivity. Experiments will be conducted both on infected cells in culture as well as on specimens derived from infected patients. Combination and sequential treatment regimens will be employed involving nucleosides (ddi, AZT, ddc) as well as other agents (rIFN alpha A, protease inhibitors, non-nucleoside reverse transcriptase inhibitors). Breakthrough viruses during therapy will be evaluated for genotypic alterations and phenotypic characteristics (e.g., syncytium capacity, cell tropism). Cells from prolonged treatment regimens will be evaluated for refractoriness to the drug in question. Molecular interactions among drugs in combination will be explored. CTL activity will be prospectively measured in patients on therapy, and the effects of drugs or drug combinations on CTL activity will be examined. These studies should help form the basis for more rational anti-HIV-1 combination therapy in future years.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA012464-25
Application #
2086059
Study Section
AIDS and Related Research Study Section 1 (ARRA)
Project Start
1979-06-01
Project End
1996-05-31
Budget Start
1995-06-01
Budget End
1996-05-31
Support Year
25
Fiscal Year
1995
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02199
Tremblay, Cecile L; Giguel, Francoise; Kollmann, Christopher et al. (2002) Anti-human immunodeficiency virus interactions of SCH-C (SCH 351125), a CCR5 antagonist, with other antiretroviral agents in vitro. Antimicrob Agents Chemother 46:1336-9
Rusconi, S; La Seta Catamancio, S; Citterio, P et al. (2000) Combination of CCR5 and CXCR4 inhibitors in therapy of human immunodeficiency virus type 1 infection: in vitro studies of mixed virus infections. J Virol 74:9328-32
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Tremblay, C L; Giguel, F; Merrill, D P et al. (2000) Marked differences in quantity of infectious human immunodeficiency virus type 1 detected in persons with controlled plasma viremia by a simple enhanced culture method. J Clin Microbiol 38:4246-8
Oh, M D; Merrill, D P; Hirsch, M S (1999) Induction and maintenance treatment regimens for HIV-1 infection in vitro. Antivir Ther 4:29-34
Martinez-Picado, J; Savara, A V; Sutton, L et al. (1999) Replicative fitness of protease inhibitor-resistant mutants of human immunodeficiency virus type 1. J Virol 73:3744-52
Merrill, D P; Martinez-Picado, J; Tremblay, C et al. (1999) Improved CD4 lymphocyte outgrowth in response to effective antiretroviral therapy. J Infect Dis 179:345-51
Tremblay, C; Merrill, D P; Chou, T C et al. (1999) Interactions among combinations of two and three protease inhibitors against drug-susceptible and drug-resistant HIV-1 isolates. J Acquir Immune Defic Syndr 22:430-6
Merrill, D P; Manion, D J; Chou, T C et al. (1997) Antagonism between human immunodeficiency virus type 1 protease inhibitors indinavir and saquinavir in vitro. J Infect Dis 176:265-8

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