IQGAP1 Negatively Regulates HIV-1 Gag Trafficking and Virion Production

IQGAP1 is a master regulator of many cellular processes, including intracellular vesicle trafficking and endocytosis. We show that depletion of IQGAP1 in a variety of cell types increases the release of HIV-1 infectious virions and that overexpression diminishes virion production, with neither affecting the early stages of infection. IQGAP1 negatively regulates the steady-state levels of HIV-1 Gag at the plasma membrane, the site of assembly. We establish that IQGAP1 interacts with both the nucleocapsid and p6 domains of Gag, and interaction with either domain is sufficient for its regulatory function. Finally, we demonstrate that IQGAP1 regulation is independent of HIV-1 Gag “late-domains” sequences required by the virus to recruit the cellular ESCRT machinery. Thus, we provide evidence that IQGAP1 is a negative regulatory factor inhibiting efficient budding of HIV-1 by reducing Gag accumulation at the plasma membrane.