In Vivo Selection of HIV-1 Variants with Reduced Susceptibility to the Protease Inhibitor L-735,524 and Related Compounds

Abstract

The human immunodeficiency virus type 1 (HIV-1) is a lentivirus that establishes a persistent, long-term infection in its human host. Like all members of this retroviral subfamily, it completes its replication cycle predominantly by budding from the plasma membrane of the infected cell. The newly formed viral particle contains a core that is composed of two copies of the viral genomic RNA and multiple copies of two precursor polyproteins. During or immediately after budding, the polyproteins are cut into subunmits by a virus-specified protease to yield the mature viral core proteins, which include the matrix, capsid and nucleocapsid proteins as well as the viral protease, reverse transcriptase and integrase enzymes. A mature core is essential for viral infectivity. Elimination of virus protease activity through directed mutation of the protease gene results in production of noninfectious mutant viral particles with immature, unprocessed cores.¹ Accordingly, the protease is a suitable target for the development of antiviral agents designed to prevent ongoing cycles of the persistent infection.