Polymorphisms in p1-p6/p6* of HIV type 1 can delay protease autoprocessing and increase drug susceptibility.
Maturation of infectious human immunodeficiency virus type 1 (HIV-1) particles requires proteolytic cleavage of structural polyproteins by 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 (PIs). Chimeric viruses carrying p1-p6/p6* sequences from patient isolates in the context of an 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 protease and the C terminus of Gag is critical for proper protease activity and mismatches between these regions can reduce viral replication and increase drug susceptibility.
ViroLogic, South San Francisco, California 94080, USA.
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N
Whitehurst
C
C
Chappey
C
C
Petropoulos
N
N
Parkin
A
A
Gamarnik
D000595:Amino Acid Sequence; D024882:Drug Resistance, Viral; D015685:Fusion Proteins, gag-pol / Q000737:chemistry / Q000235:genetics*; D015683:Gene Products, gag / Q000737:chemistry / Q000235:genetics*; D016333:HIV Protease / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics*; D008969:Molecular Sequence Data; D011110:Polymorphism, Genetic; D011498:Protein Precursors / Q000737:chemistry / Q000235:genetics*; D014779:Virus Replication
D015685:Fusion Proteins, gag-pol; D015683:Gene Products, gag; D017320:HIV Protease Inhibitors; D011498:Protein Precursors; C059767:p55 gag precursor protein, Human immunodeficiency virus 1; D016333:HIV Protease