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13th International HIV Drug Resistance Workshop8–12 June 2004, Tenerife Sur-Costa Adeje, Canary Islands, Spain |
BACKGROUND: HIV-1 co-receptor antagonists represent a new opportunity for antiretroviral intervention. In a prior retrospective analysis of a Phase I/II study of the CXCR4 antagonist AMD3100, several subjects with X4R5-tropic virus at baseline developed R5-tropic virus on treatment. The present study was conducted to determine whether baseline X4R5 viruses represent mixed mono-tropic or pure dual-tropic variants and to describe changes in virus populations associated with the addition and removal of drug pressure.
METHODS: Virus populations at baseline (day 0), on treatment (day 11) and off treatment (days 18, 39) were characterized by determining the co-receptor tropism of 25–40 envelope clones per time point using an envelope pseudo-virus infectivity assay. Gp160 sequences were determined for at least 10 clones per time point.
RESULTS: Clonal analysis was performed on the virus populations of three study subjects exhibiting X4R5 tropism at baseline and R5 tropism on treatment. In patient one, co-receptor utilization was 66%-R5 and 34%-X4 at baseline, 100%-R5 at day 11 (on treatment) and day 18 (off treatment), returning to 65%-R5 and 35%-X4 on day 39 (off treatment). In patient two, co-receptor utilization was 55%-R5, 10%-X4 and 35%-dual at baseline, predominantly R5 at day 11 (97%) and day 18 (92%), returning to 32%-R5, 3%- X4 and 65%-dual by day 39. In patient three, the coreceptor utilization was 67%-R5, 27%-X4 and 6%- dual at baseline, 100%-R5 at day 11, predominantly R5 at day 18 (97%), remaining R5 (100%) at day 39. Sequence analysis of individual clones distinguished R5 viruses from X4 and dual-tropic viruses, largely based on differences in the V3 region. Envelope sequences selected under drug pressure were closely related to variants pre-existing in the baseline population.
CONCLUSIONS: During a short course of monotherapy with AMD3100, X4- and dual-tropic variants were suppressed, accompanied by a concomitant increase in the proportion of R5-tropic variants in the viral population. The suppression of dual-tropic variants merits additional investigation as this observation could have significant implications for the use of CXCR4 inhibitors in the clinic. Shifts in co-receptor tropism, both on and off treatment most likely result from selection of pre-existing variants from within the baseline quasispecies.
PRESENTING AUTHOR: W Huang
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2004-06-08
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