Molecular Mechanisms Of HIV-1 Maturation And Host Factor Utilization

Abstract

HIV-1 is the major etiologic agent of AIDS, for which there is presently no cure or vaccine. The capsid is the structural component of HIV-1: it serves many functions during viral replication, and it is the product of maturation. Particle maturation is a critical step in the HIV-1 replication cycle that requires proteolytic cleavage of the Gag polyprotein into its constitutive proteins: matrix (MA), capsid (CA), nucleocapsid (NC), and p6. Accurate and efficient cleavage of Gag is essential for virion infectivity: inhibitors of the viral protease are potent antivirals, and substitutions in Gag that prevent its cleavage result in reduced HIV-1 infectivity. When cleavage between MA and CA is blocked, the uncleaved MA-CA protein potently reduces HIV-1 infectivity. In this dissertation, I show that uncleaved MA-CA and cleaved CA proteins coassemble to form capsids that are impaired for nuclear entry, and my genetic analysis suggests that the coassembled capsids are tethered to the target cell membrane upon entry. My results suggest that small amounts of partially-processed Gag subunits coassemble with CA during virion maturation, resulting in impaired capsid functions. This knowledge may be useful in the development of new anti-HIV-1 therapeutics targeting maturation.