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

Creator(s)

Sarah Ho, University of Florida College of Medicine
Roxana M. Coman, University of Florida College of Medicine
Joshua C. Bunger, University of Florida College of Medicine
Stephanie L. Rose, University of Florida College of Medicine
Patricia O'Brien, University of Florida College of Medicine
Isabel Munoz, University of Florida College of Medicine
Ben M. Dunn, University of Florida College of Medicine
John W. Sleasman, Quillen-Dishner College of Medicine
Maureen M. Goodenow, University of Florida College of Medicine

Document Type

Article

Publication Date

9-1-2008

Description

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.

Copyright Statement

© 2008 Elsevier Inc. Open access under CC BY-NC-ND license

Creative Commons License

This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License.

Citation Information

Ho, Sarah; Coman, Roxana M.; Bunger, Joshua C.; Rose, Stephanie L.; O'Brien, Patricia; Munoz, Isabel; Dunn, Ben M.; Sleasman, John W.; and Goodenow, Maureen M.. 2008. 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. Virology. Vol.378(2). 272-281. https://doi.org/10.1016/j.virol.2008.05.029 PMID: 18599104 ISSN: 0042-6822