|
|||||
|
|
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 |
|
| Authors: | Ho Sarah K Coman Roxana M Bunger Joshua C Rose Stephanie L O'Brien Patricia Munoz Isabel Dunn Ben M Sleasman John W Goodenow Maureen M |
| Affiliation: | a Department of Pathology, Immunology, and Laboratory Medicine, Box 103633, University of Florida College of Medicine, 1376 Mowry Road, Gainesville, FL 32610-3633, USA b Department of Biochemistry and Molecular Biology, Box 103633, University of Florida College of Medicine, 1376 Mowry Road, Gainesville, FL 32610-3633, USA c Department of Pediatrics, Division of Allergy, Immunology, and Rheumatology, College of Medicine, University of South Florida, USA d All Children's Hospital, St. Petersburg, Florida 33701, USA |
| Abstract: | Regions of HIV-1 gag between p2 and p6Gag/p6Pol, 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/p7NC cleavage site and p7NC, 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. |
| Keywords: | Fitness Protease, Pi resistance |
| 本文献已被 ScienceDirect PubMed 等数据库收录！ | |