HIV-1 escape to CCR5 coreceptor antagonism through selection of CXCR4-using variants in vitro

Moncunill, Gemma; Armand-Ugón, Mercedes; Pauls, Eduardo; Clotet, Bonaventura; Esté, José A

AIDS:
doi: 10.1097/QAD.0b013e3282f303e6
Basic Science
Abstract

Background: HIV-1 coreceptor switch from CCR5 to CXCR4 is associated with disease progression and AIDS. Selection of resistant HIV-1 to CCR5 agents in cell culture has often occurred in the absence of coreceptor switch. With CCR5 antagonists currently in clinical trials, their impact on coreceptor use is still in doubt.

Methods: Six R5 HIV-1 strains were passaged in lymphoid cells expressing high CXCR4 and low CCR5, in the absence or presence of CCR5 inhibitors (TAK-779, mAb 2D7 and CCL5). AMD3100, zidovudine and lamivudine were used as controls. Phenotype and genotype changes as well as virus coreceptor use were evaluated.

Results: In the absence of drug pressure, three out of six strains expanded their coreceptor use to CXCR4 at different times, suggesting that not all virus strains had the capacity to do so. Lowering the replication rate with a suboptimal concentration of different anti-HIV agents (reverse transcriptase inhibitors or CCR5 agents) delayed coreceptor switch. However, virus breakthrough was observed earlier in the presence of CCR5-targeting agents than in presence of reverse transcriptase inhibitors and was associated with a change in sensitivity to TAK-779 or AMD3100, virus coreceptor expansion to CXCR4 and changes in the V3 loop region of gp120.

Conclusion: Our results suggest that HIV-1 may escape CCR5 drug pressure through coreceptor switch. Experimental conditions strongly determine the outcome of CCR5 drug pressure in cell culture. A cell culture model of the evolution of HIV-1 coreceptor use may be relevant to assess the propensity of clinical isolates to develop resistance through coreceptor change.

Author Information

From the Retrovirology Laboratory IrsiCaixa and AIDS Unit, Hospital Germans Trias i Pujol, Badalona, Spain.

Received 21 June, 2007

Revised 24 September, 2007

Accepted 4 October, 2007

Correspondence to José A. Esté, Retrovirology Laboratory IrsiCaixa and AIDS Unit, Hospital Germans Trias i Pujol, 08916 Badalona, Spain. Tel: +34 934656374; fax: +34 934653968; e-mail: jaeste@irsicaixa.es

© 2008 Lippincott Williams & Wilkins, Inc.