Abstract

A multi-institutional group seeks to renew funding to support the continuation of its cooperative effort to develop novel classes of drugs which inhibit HIV-1 replication. This proposal consists of 5 projects that represent an integrated program using a rational approach to develop anti-HIV-1 drugs. Three of the projects based at academic institutions will apply fundamental knowledge to the development of biochemical and cell based assays for key components of HIV-1. Specific targets include the HIV-1 integrase, vpr protein, capsid packaging functions and ribonucleaseH. Work on reverse transcriptase and gp120-CD4 interactions will continue as well as work on selected new areas in the design of protease inhibitors. The fourth project based at an academic institution will address problems of resistance of HIV-1 to anti-viral therapy. To this end, fundamental studies of drug resistance will be carried out. Strains of SIV resistant to anti-viral drugs will be made, and an animal model, SIVMac, will be used to develop means of overcoming clinical resistance. The industrial partner is well equipped to apply the latest methods of drug development to HIV-1 therapy and is experienced in bringing drugs from the development state to clinical trials. The group includes three laboratories from the Dana-Farber Cancer Institute, one laboratory from Columbia University, and scientists at SmithKline Beecham Pharmaceuticals. The group also includes sub-projects to be carried out at the Delta Regional Primate Research Center and at the Albert Einstein College of Medicine. Together these institutions provide a pool of research unattainable at any single institution. The experience and proven ability of this group to work together productively insures that this program will continue to be successful.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AI024845-09
Application #
2062778
Study Section
Special Emphasis Panel (SRC (41))
Project Start
1991-09-01
Project End
1995-08-31
Budget Start
1994-09-01
Budget End
1995-08-31
Support Year
9
Fiscal Year
1994
Total Cost
Indirect Cost

  Institution

Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
149617367
City
Boston
State
MA
Country
United States
Zip Code
02215

  Publications

Ruprecht, R M; Baba, T W; Liska, V et al. (1999) Oral transmission of primate lentiviruses. J Infect Dis 179 Suppl 3:S408-12
Trichel, A M; Roberts, E D; Wilson, L A et al. (1997) SIV/DeltaB670 transmission across oral, colonic, and vaginal mucosae in the macaque. J Med Primatol 26:3-10
Yang, G; Song, Q; Charles, M et al. (1996) Use of chimeric human immunodeficiency virus types 1 and 2 reverse transcriptases for structure-function analysis and for mapping susceptibility to nonnucleoside inhibitors. J Acquir Immune Defic Syndr Hum Retrovirol 11:326-33
Wainberg, M A; Drosopoulos, W C; Salomon, H et al. (1996) Enhanced fidelity of 3TC-selected mutant HIV-1 reverse transcriptase. Science 271:1282-5
Reicin, A S; Ohagen, A; Yin, L et al. (1996) The role of Gag in human immunodeficiency virus type 1 virion morphogenesis and early steps of the viral life cycle. J Virol 70:8645-52
Orsini, M J; Debouck, C M; Webb, C L et al. (1996) Extracellular human immunodeficiency virus type 1 Tat protein promotes aggregation and adhesion of cerebellar neurons. J Neurosci 16:2546-52
Churchill, M J; Moore, J L; Rosenberg, M et al. (1996) The rev-responsive element negatively regulates human immunodeficiency virus type 1 env mRNA expression in primate cells. J Virol 70:5786-90
Orsini, M J; Garcia-Martinez, L F; Mavankal, G et al. (1996) Purification and functional characterization of wild-type and mutant HIV-1 and HIV-2 Tat proteins expressed in Escherichia coli. Protein Expr Purif 8:238-46
Reicin, A S; Paik, S; Berkowitz, R D et al. (1995) Linker insertion mutations in the human immunodeficiency virus type 1 gag gene: effects on virion particle assembly, release, and infectivity. J Virol 69:642-50
Berkowitz, R D; Hammarskjold, M L; Helga-Maria, C et al. (1995) 5' regions of HIV-1 RNAs are not sufficient for encapsidation: implications for the HIV-1 packaging signal. Virology 212:718-23

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