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Combined Antiretroviral Therapy and Immune Pressure Lead to In Vivo HIV-1 Recombination With Ancestral Viral Genomes

Buzón, Maria José PhD*; Wrin, Terri BS; Codoñer, Francisco M PhD*; Dalmau, Judith MSc*; Phung, Pham BS; Bonjoch, Anna MD, PhD; Coakley, Eoin MD; Clotet, Bonaventura MD, PhD*‡; Martinez-Picado, Javier PhD

JAIDS Journal of Acquired Immune Deficiency Syndromes: June 1st, 2011 - Volume 57 - Issue 2 - p 109-117
doi: 10.1097/QAI.0b013e318215ab0a
Basic and Translational Science

Background: Studies on drug interruption have provided new insights on the adaptive evolution of rebounding HIV-1 during antiretroviral pressure. We investigated the origin of new viral variants after discontinuation of protease (PR) inhibitors as a treatment remained exclusively based on reverse transcriptase inhibitors, and whether drug susceptibility, viral fitness, and neutralizing antibodies could be major driving forces for the evolution of virus populations.

Methods: The study comprised 3 treatment-experienced subjects. Phylogenetic analysis of the PR, reverse transcriptase, and the viral envelope were carried out to ascertain the origin of the new viral variants with samples obtained over a 10-year period before and after a PR inhibitor withdrawal. In addition, drug susceptibility, replication capacity, and neutralization assays were performed.

Results: New viral variants from all 3 subjects were derived through recombination with ancestral quasispecies. Computerized recombination models confirmed these results. Recombination was demonstrated by increased replication capacity, decreased drug susceptibility, and neutralization of ancestral virus envelope by contemporaneous plasma samples.

Conclusions: These findings demonstrate the relevance of HIV-1 reservoirs in adaptive evolution throughout recombination in response to selective pressure, such as antiretroviral therapy and immune responses. This result might assist in the design of new treatment strategies for patients experiencing treatment failure.

From the *Institut de Recerca de la SIDA IrsiCaixa, Hospital Universitari “Germans Trias i Pujol”, Universitat Autònoma de Barcelona (UAB), Badalona, Spain; †Monogram Biosciences, South San Francisco, CA; ‡Fundació de Lluita contral la SIDA, Badalona, Spain; and §Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.

Received for publication January 5, 2011; accepted February 14, 2011.

Supported by the Spanish AIDS network “Red Temática Cooperativa de Investigación en SIDA” (RD06/0006) and by funding from the European Community's Seventh Framework Program (FP7/2007-2013) under the project “Collaborative HIV and Anti-HIV Drug Resistance Network (CHAIN)” (grant agreement no. 223131). M.J.B. was supported by Agència de Gestió d'Ajuts Universitaris i de Recerca from Generalitat de Catalunya and the European Social Fund. F.M.C was supported by the Marie Curie European Reintegration Grant number 238885, “HIV Coevolution”, and by the European Commission Framework 7 Program.

The authors have no conflicts of interest to disclose.

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Correspondence to: Javier Martinez-Picado, PhD, IrsiCaixa Foundation, Hospital Germans Trias i Pujol, Ctra. de Canyet s/n, 08916 Badalona, Spain (e-mail: jmpicado@irsicaixa.es).

© 2011 Lippincott Williams & Wilkins, Inc.