18th International HIV Drug Resistance Workshop Basic Principles & Clinical Implications June 9–13 2009, Fort Myers, Florida, USA

TRANSITIONS FROM CCR5 TO CXCR4 USE IN THE ABSENCE OF ANTIRETROVIRAL DRUG PRESSURE PROCEED INCREMENTALLY AND MAY OCCUR THROUGH A MULTITUDE OF GENETIC PATHWAYS

Antivir Ther 2009; 14 Suppl 1:A15 (abstract no. 13)

W Huang¹, E Coakley¹, J Toma¹, E Stawiski¹, A Frantzell¹, H Schuitemaker², CJ Petropoulos¹ and AB van ‘t Wout^2
1Monogram Biosciences, South San Francisco, CA, USA; ²Department of Experimental Immunology, Center for Infectious Diseases and Immunity Amsterdam (CINIMA), Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands

BACKGROUND: The emergence of HIV subpopulations that utilize the CXCR4 coreceptor is clinically important yet poorly understood. CXCR4 use is prognostic for disease progression, negatively predictive for response to CCR5 antagonists and represents a prevalent escape pathway for CCR5 inhibitor treatment. To advance our understanding of the acquisition of CXCR4 use, we characterized coreceptor utilization along with envelope clone sequences derived from patient virus populations that evolved the ability to use CXCR4 in the absence of antiretroviral drug pressure.

METHODS: Longitudinal plasma samples were obtained from eight treatment-naïve subjects with previously documented tropism switches (NSI to SI). Envelope clones were isolated from different time points for each subject. Coreceptor tropism was assigned by Trofile and envelope sequences were determined using conventional methods.

RESULTS: Virus populations at the time of the coreceptor switch comprised mixtures of R5-and dual-tropic clones. The proportion of dual tropic clones in virus populations and their ability to use CCR5 and CXCR4 varied by subject. Dual-X clones that use CXCR4 efficiently were identified in all eight subjects; dual-R clones that use CXCR4 inefficiently appeared in six patients and presented prior to, or concurrently with, dual-X tropic clones. Phylogenetic analysis of full-length envelope sequences demonstrated that emerging dual-X variants exhibited limited diversity and were markedly divergent from R5 and dual-R clones in some, but not all cases. Generally, efficient CXCR4 use required multiple amino acid changes in the V3 loop, but few discernable patterns were shared among subjects. The presence of positively charged amino acids at positions 11/25 and the absence of potential N-linked glycosylation sites in V3 were associated with, but not unique to, CXCR4 use.

CONCLUSIONS: Detailed characterization of emerging CXCR4-using variants in the virus populations of eight individuals indicates that HIV uses a multitude of mutational pathways to change from CCR5 to CXCR4 use. Furthermore, our observations indicate that CCR5 to CXCR4 transitions are incremental, not quantum, and are consistent with the ‘R5, dual-R, dual-X’ model that we have proposed to describe the evolution of CXCR4 use from R5-tropic virus populations.

2009-06-09
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