JVI Accepts, published online ahead of print on 10 June 2009

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J. Virol. doi:10.1128/JVI.00003-09
Copyright (c) 2009, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Positive Selection Pressure Introduces Secondary Mutations at the Gag Cleavages Sites in HIV-1 Harboring Major Protease Resistance Mutations

Søren Banke^*, Marie R. Lillemark, Jan Gerstoft, Niels Obel, and Louise Bruun Jørgensen

Virus BL-3 lab., Statens Serum Institut, Artillerivej 5, 2300 Kbh. S, Denmark; Department of infectious Diseases, Rigshospitalet University of Copenhagen

^* To whom correspondence should be addressed. Email: SBK{at}ssi.dk.

HIV-1 protease inhibitors (PIs) specifically target the HIV-1 protease enzyme. Mutations in the enzyme can result in PI resistance (termed PI mutations); however, mutations in the HIV-1 gag region, the substrate for the protease enzyme, might also lead to PI resistance. We analyzed gag and pol sequence data from 313 HIV-1-infected patients: 160 treatment-naïve patients, 93 patients failing antiretroviral treatment that included a PI (with no major PI mutations), and 60 patients failing antiretroviral treatment that included a PI (with major PI mutations). Additional sequences from 13 patients were included for longitudinal analysis. We assessed positive selection pressure on the gag/protease region using a test for the overall influence of positive selection and a total of five tests to identify positively selected single codons. We found that positive selection pressure was the driving evolutionary force for the gag region in all three patient groups. An increase in positive selection was observed in gag cleavage site regions p7/p1/p6 only after the acquisition of major PI mutations, suggesting that amino acids in gag cleavage sites under positive selection pressure could function as compensatory mutations for major PI mutations in the protease region. Isolated gag mutations did not appear to confer PI resistance, but mutations in the gag cleavage sites could substitute for minor PI resistance mutations in the protease region.

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