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Journal of Virology, October 2001, p. 9644-9653, Vol. 75, No. 20
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.20.9644-9653.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Resistance to Nucleoside Analog Reverse Transcriptase Inhibitors Mediated by Human Immunodeficiency Virus Type 1 p6 Protein

Solange Peters,1 Miguel Muñoz,2 Sabine Yerly,3 Victor Sanchez-Merino,4 Cecilio Lopez-Galindez,4 Luc Perrin,3 Brendan Larder,5 Dusan Cmarko,6 Stanislav Fakan,6 Pascal Meylan,2 and Amalio Telenti1,2,*

Division of Infectious Diseases1 and Institute of Microbiology,2 University Hospital, and Center of Electron Microscopy,6 Lausanne, and Division of Infectious Diseases, University Hospital, Geneva,3 Switzerland; Centro Nacional de Biologìa Fundamental, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain4; and Virco, Cambridge, United Kingdom5

Received 6 April 2001/Accepted 9 July 2001

Resistance of human immunodeficiency virus type 1 (HIV-1) to antiretroviral agents results from target gene mutation within the pol gene, which encodes the viral protease, reverse transcriptase (RT), and integrase. We speculated that mutations in genes other that the drug target could lead to drug resistance. For this purpose, the p1-p6gag-p6pol region of HIV-1, placed immediately upstream of pol, was analyzed. This region has the potential to alter Pol through frameshift regulation (p1), through improved packaging of viral enzymes (p6Gag), or by changes in activation of the viral protease (p6Pol). Duplication of the proline-rich p6Gag PTAP motif, necessary for late viral cycle activities, was identified in plasma virus from 47 of 222 (21.2%) patients treated with nucleoside analog RT inhibitor (NRTI) antiretroviral therapy but was identified very rarely from drug-naïve individuals. Molecular clones carrying a 3-amino-acid duplication, APPAPP (transframe duplication SPTSPT in p6Pol), displayed a delay in protein maturation; however, they packaged a 34% excess of RT and exhibited a marked competitive growth advantage in the presence of NRTIs. This phenotype is reminiscent of the inoculum effect described in bacteriology, where a larger input, or a greater infectivity of an organism with a wild-type antimicrobial target, leads to escape from drug pressure and a higher MIC in vitro. Though the mechanism by which the PTAP region participates in viral maturation is not known, duplication of this proline-rich motif could improve assembly and packaging at membrane locations, resulting in the observed phenotype of increased infectivity and drug resistance.

* Corresponding author. Mailing address: Division of Infectious Diseases, CHUV, 1011 Lausanne, Switzerland. Phone: 41 21 314 0550. Fax: 41 21 314 1008. E-mail: amalio.telenti{at}chuv.hospvd.ch.

Journal of Virology, October 2001, p. 9644-9653, Vol. 75, No. 20
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.20.9644-9653.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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