This application proposes to study the important question of how Gag reaches the plasma membrane. Preliminary studies in the P.I.'s laboratory suggest that, with the exception of the myristylation signal, MA, is entirely dispensable for efficient viral particle production and that the MA core subdomain primarily governs the specificity rather than the efficiency of Gag membrane binding. Preliminary data also indicate that mutants which lack up to 90% of MA can replicate efficiently in certain cells if a defect in Env incorporation is correct. The goals of the study are (AIM 1) to determine the contribution of MA: to the kinetics and specificity of Gag membrane targeting; to the distinct lipid composition of the HIV virion membrane; and to association of MA with the cytoskeleton.
In AIM 2, the role of myristylation and MA phosphorylation in regulating membrane insertion of the N-terminal myristyl group of MA (the myristyl switch hypothesis) will be examined using replication-competent MA-deleted viruses and other mutants as tools.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI042510-01
Application #
2542930
Study Section
AIDS and Related Research Study Section 3 (ARRC)
Project Start
1998-01-01
Project End
2002-12-31
Budget Start
1998-01-01
Budget End
1998-12-31
Support Year
1
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
149617367
City
Boston
State
MA
Country
United States
Zip Code
02215
Song, Erwei; Lee, Sang-Kyung; Wang, Jie et al. (2003) RNA interference targeting Fas protects mice from fulminant hepatitis. Nat Med 9:347-51
Dorfman, Tatyana; Popova, Elena; Pizzato, Massimo et al. (2002) Nef enhances human immunodeficiency virus type 1 infectivity in the absence of matrix. J Virol 76:6857-62
Gottlinger, H G (2001) The HIV-1 assembly machine. AIDS 15 Suppl 5:S13-20
Paillart, J C; Gottlinger, H G (1999) Opposing effects of human immunodeficiency virus type 1 matrix mutations support a myristyl switch model of gag membrane targeting. J Virol 73:2604-12