Gag determinants of fitness and drug susceptibility in protease inhibitor-resistant human immunodeficiency virus type 1.
Mutations can accumulate in the protease and gag genes of human immunodeficiency virus in patients who fail therapy with protease inhibitor drugs. Mutations within protease, the drug target, have been extensively studied. Mutations in gag have been less well studied, mostly concentrating on cleavage sites. A retroviral vector system has been adapted to study full-length gag, protease, and reverse transcriptase genes from patient-derived viruses. Patient plasma-derived mutant full-length gag, protease, and gag-protease from a multidrug-resistant virus were studied. Mutant protease alone led to a 95% drop in replication capacity that was completely rescued by coexpressing the full-length coevolved mutant gag gene. Cleavage site mutations have been shown to improve the replication capacity of mutated protease. Strikingly, in this study, the matrix region and part of the capsid region from the coevolved mutant gag gene were sufficient to achieve full recovery of replication capacity due to the mutant protease, without cleavage site mutations. The same region of gag from a second, unrelated, multidrug-resistant clinical isolate also rescued the replication capacity of the original mutant protease, suggesting a common mechanism that evolves with resistance to protease inhibitors. Mutant gag alone conferred reduced susceptibility to all protease inhibitors and acted synergistically when linked to mutant protease. The matrix region and partial capsid region of gag sufficient to rescue replication capacity also conferred resistance to protease inhibitors. Thus, the amino terminus of Gag has a previously unidentified and important function in protease inhibitor susceptibility and replication capacity.
Parry
Chris M
CM
UCL/MRC Centre for Medical Molecular Virology, Division of Infection and Immunity, UCL, Windeyer Institute, 46 Cleveland Street, London W1T 4JF, United Kingdom. chris.parry@hpa.org.uk
Kohli
Arinder
A
Boinett
Christine J
CJ
Towers
Greg J
GJ
McCormick
Adele L
AL
Pillay
Deenan
D
D001483:Base Sequence; D018432:Drug Resistance, Multiple; D024882:Drug Resistance, Viral; D015658:HIV Infections; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000737:chemistry / Q000502:physiology*; D006801:Humans; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000235:genetics; D009154:Mutation; D014779:Virus Replication; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000235:genetics*
D017320:HIV Protease Inhibitors; D050505:Mutant Proteins; D054301:gag Gene Products, Human Immunodeficiency Virus