[20] REDUCED FITNESS OF HIV-1 THAT ARE RESISTANT TO CXCR4 ANTAGONISTS DUE TO ALTERATIONS IN GP120 FUNCTION

5th International Workshop on HIV Drug Resistance & Treatment Strategies

4-8 June 2001, Scottsdale, Arizona

[TITLE:] REDUCED FITNESS OF HIV-1 THAT ARE RESISTANT TO CXCR4 ANTAGONISTS DUE TO ALTERATIONS IN GP120 FUNCTION

[AUTHOR(S):] JA Esté¹, ME Quiñones-Mateu², J Barretina¹, M Armand-Ugon¹, D Schols³, J Blanco¹, A Gutierrez¹, B Clotet¹ and E De Clercq³
¹ Retrovirology Laboratory IrsiCaixa, Hospital Universitari Germans Trias i Pujol, Universitat Autonoma de Barcelona, Badalona, Spain; ² Department of Virology, Lerner Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA; and ³ Rega Institute for Medical Research, Katholieke Universiteit Leuven, Leuven, Belgium
Antivir Ther. 2001;6 Suppl 1:18

HIV-1 strains with a syncytium-inducing phenotype that use CXCR4 (X4 strains) have been associated with faster disease progression and AIDS. Antiviral agents designed to block CXCR4 may prevent the emergence of X4 virus but resistant strains that maintain the X4 phenotype can be raised by sequential passage in vitro in cell culture. Here, we demonstrate that a laboratory adapted strain (NL4-3) and a cloned clinical isolate (CI-1) of HIV-1, cultured in the presence of the CXCR4 antagonist AMD3100, became resistant to the compound without a change in coreceptor use. Conversely, a clinical isolate made resistant to AMD3100, had switched co-receptor use from X4 to R5. When dual infection competition/ heteroduplex tracking assays were performed, all AMD3100-resistant strains, regardless of co-receptor use, had a significantly diminished fitness as compared to the corresponding wild-type viruses. Single virus infections, at the same multiplicity of infection, also indicated that the wild-type virus strains had better replicative capacity than the corresponding drugresistant virus strains. Virus-infected cells expressing viral gp120 were prone to cell death with lower viral replication, if infected with AMD3100-resistant, as compared to wild-type, virus strains. AMD3100-resistant virus has reduced fitness, an observation that may have significant implications in the treatment of HIV-infected individuals with this class of anti-HIV agents.

PRESENTING AUTHOR: JA Esté

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