Polymorphisms in p1-p6/p6* of HIV-1 Can Delay PR Autoprocessing and Increase Drug Susceptibility

N. WHITEHURST, C. CHAPPEY, C. PETROPOULOS, N. PARKIN, AND A. GAMARNIK

AIDS RESEARCH AND HUMAN RETROVIRUSES

Año: 2003 vol. 19 p. 779 - 784

0889-2229

Maturation of infectious human immunodeficiency virus type 1 (HIV-1) particles requires proteolytic cleavage of the structural polyproteins by the viral protease. Inhibition of protease is a powerful tool for the treatment of HIV infection. Using a well-established phenotypic drug susceptibility assay, we found that sequences outside of the protease gene can modulate the susceptibility to protease inhibitors (PI). Chimeric viruses carrying p1-p6/p6* sequences from patient isolates in the context of a NL4-3 molecular clone exhibited increased PI susceptibility. Furthermore, this phenotype was associated with a delay in protease autoprocessing in virions and a reduction in replication capacity. We propose that the interplay between PR and the C-terminus of Gag is critical for proper protease activity and mismatches between these regions can reduce viral infectivity and increase drug susceptibility.