Drug-associated changes in amino acid residues in Gag p2, p7NC, and p6Gag/p6Pol in human immunodeficiency virus type 1 (HIV-1) display a dominant effect on replicative fitness and drug response

被引：26

作者：

Ho, Sarah K. ^{[1
]}

Coman, Roxana M. ^{[1
]}

Bunger, Joshua C. ^{[1
]}

Rose, Stephanie L. ^{[1
]}

O'Brien, Patricia ^{[1
]}

Munoz, Isabel ^{[1
]}

Dunn, Ben M. ^{[2
]}

Sleasman, John W. ^{[3
,4
]}

Goodenow, Maureen M. ^{[1
]}

机构：

[1] Univ Florida, Coll Med, Dept Pathol Immunol & Lab Med, Gainesville, FL 32601 USA

[2] Univ Florida, Coll Med, Dept Biochem & Mol Biol, Gainesville, FL 32601 USA

[3] Univ S Florida, Dept Pediat, Div Allergy Immunol & Rheumatol, Tampa, FL 33620 USA

[4] Univ S Florida, All Childrens Hosp, St Petersburg, FL 33701 USA

来源：

VIROLOGY | 2008年 / 378卷 / 02期

关键词：

fitness; protease; Pi resistance;

D O I：

10.1016/j.virol.2008.05.029

中图分类号：

Q93 [微生物学];

学科分类号：

071005 ; 100705 ;

摘要：

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. (C) 2008 Elsevier Inc. All rights reserved.

引用

页码：272 / 281

页数：10

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