HIV-1 Assembly, Maturation, and Drug Resistance

The Freed lab's research focuses on various aspects of HIV-1 particle assembly, budding, envelope glycoprotein (Env) trafficking, and incorporation into virus particles, particle maturation, and post-entry events. They also have a long-standing interest in HIV-1 drug resistance. In this seminar on November 6, 2023, two projects will be discussed in detail: the requirement for neutral sphingomyelinase 2 (nSMase2) in HIV-1 maturation and the basis for resistance to integrase strand-transfer inhibitors (INSTIs). HIV-1 assembly takes place at the inner leaflet of the plasma membrane in highly ordered membrane microdomains. The size and stability of these microdomains are regulated by the activity of nSMase2. Disrupting nSMase2 impairs HIV-1 Gag and GagPol processing, resulting in a profound impairment in particle maturation and infectivity. These findings suggest a previously undescribed role for nSMase2 in the morphogenesis and maturation of primate lentivirus. Some individuals treated with INSTIs experience virological failure in the absence of resistance mutations in IN. To elucidate INSTI resistance mechanisms and pathways, long-term passaging of lab-adapted and primary viral isolates was performed with escalating concentrations of the INSTI dolutegravir (DTG). HIV-1 became resistant to DTG by sequentially acquiring mutations in Env and Gag-nucleocapsid (NC) in the absence of resistance mutations in IN. These findings demonstrate that, in cell culture, a combination of mutations in Env and NC can confer high-level resistance to INSTIs in the absence of IN mutations.