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.
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