NOTES Human Immunodeficiency Virus Type 1 Matrix Inhibits and Confers Cooperativity on Gag Precursor-Membrane Interactions

Human immunodeficiency virus type 1 (HIV-1) Gag multimerization and membrane binding are required for particle formation. However, it is unclear what constitutes a minimal plasma membrane-specific targeting signal and what role the matrix (MA) globular head and other Gag domains play in membrane targeting. Here, we use membrane flotation and microscopic analysis of Gag deletion mutants to demonstrate that the HIV-1 MA globular head inhibits a plasma membrane-specific targeting signal contained within the six amino-terminal MA residues. MA-mediated inhibition is relieved by concentration-dependent Gag multimerization and imparts a high degree of cooper-ativity on Gag-membrane association. This cooperativity may confer temporal and spatial regulation on HIV-1 assembly. Various protein, nucleic acid, and lipid components are assem-bled during retroviral particle morphogenesis, but the Gag pre-cursor is the only viral protein that is required for particle forma-tion. While most retroviruses assemble on cellular membranes, the temporal relationship between the association of Gag with itself and the association of Gag with membranes can vary. Hu-man immunodeficiency virus type 1 (HIV-1) Gag multimerization occurs primarily on cellular membranes (3, 23), but some degre