Drug-associated changes in amino acid residues in Gag p2, p7(NC), and p6(Gag)/p6(Pol) in human immunodeficiency virus type 1 (HIV-1) display a dominant effect on replicative fitness and drug response.
Regions of HIV-1 gag between p2 and p6(Gag)/p6(Pol), in addition to protease (PR), develop genetic diversity in HIV-1 infected individuals who fail to suppress virus replication by combination protease inhibitor (PI) therapy. To elucidate functional consequences for viral replication and PI susceptibility by changes in Gag that evolve in vivo during PI therapy, a panel of recombinant viruses was constructed. Residues in Gag p2/p7(NC) cleavage site and p7(NC), combined with residues in the flap of PR, defined novel fitness determinants that restored replicative capacity to the posttherapy virus. Multiple determinants in Gag have a dominant effect on PR phenotype and increase susceptibility to inhibitors of drug-resistant or drug-sensitive PR genes. Gag determinants of drug sensitivity and replication alter the fitness landscape of the virus, and viral replicative capacity can be independent of drug sensitivity. The functional linkage between Gag and PR provides targets for novel therapeutics to inhibit drug-resistant viruses.
Ho
Sarah K
SK
Department of Pathology, Immunology, and Laboratory Medicine, Box 103633, University of Florida College of Medicine, 1376 Mowry Road, Gainesville, FL 32610-3633, USA.
Coman
Roxana M
RM
Bunger
Joshua C
JC
Rose
Stephanie L
SL
O'Brien
Patricia
P
Munoz
Isabel
I
Dunn
Ben M
BM
Sleasman
John W
JW
Goodenow
Maureen M
MM
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000235:genetics*; D002460:Cell Line; D024882:Drug Resistance, Viral; D016333:HIV Protease / Q000235:genetics; D017320:HIV Protease Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008969:Molecular Sequence Data; D011995:Recombination, Genetic; D014779:Virus Replication / Q000187:drug effects*; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000235:genetics*
D017320:HIV Protease Inhibitors; D054301:gag Gene Products, Human Immunodeficiency Virus; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1