Resistance to Entry Inhibitors
Session Day and Time: Tuesday 1:30 - 3:30 pm
Room: Hall A
Background: The ability of CCR5-using (R5) HIV-1 to undergo phenotypic evolution to acquire CXCR4 usage (X4) is of great concern in the development of CCR5-specific viral entry inhibitors because of the association of X4 virus outgrowth with accelerated disease progression. Therefore, we sought to evaluate the potential for in vivo HIV-1 escape from the small molecule CCR5 antagonist, SCH-C (SCH 351125), in the SCID-hu Thy/Liv mouse model of HIV-1 infection.
Methods: We inoculated the Thy/Liv implants of SCID-hu mice (7 mice/group) with 5,000 TCID50 of either HIV-1 CC1/85 (R5) or CC2/86 (R5X4) and allowed the infection to become established for 3 wks before initiating treatment with SCH-C by twice daily oral gavage at 30 mg/kg/day. These sequential primary isolates were chosen because they were obtained from a patient whose initial R5 virus emerged as R5X4 virus a few months before a significant decline in CD4+ T-cell counts. Dosing with SCH-C was performed for 4 or 8 wks after which implants were collected for viral load (p24 and HIV-1 RNA) assays and analysis of thymocyte subsets by multi-parameter flow cytometry.
Results: Treatment of mice with SCH-C for 4 wks reduced implant p24 and viral RNA by 96% (350 versus 12 pg p24 and 100,000 versus 4,000 copies of viral RNA per 106 cells) in CC1/85-infected implants. Similar inhibition (380 versus 10 pg p24 and 40,000 vs 2,000 copies) was observed after 8 wks of SCH-C treatment. In contrast, treatment had no effect on the replication of CC2/86 in mice from the same SCID-hu cohort (720 pg p24 and 400,000 copies in untreated mice versus 1,200 pg p24 and 1,000,000 copies in treated mice), and the extent of thymocyte depletion was similar in both groups. Virus isolated from CC1/85-infected implants of treated mice had neither evidence of in vitro resistance to SCH-C nor CXCR4 usage in U87-CD4-CXCR4 cell-based coreceptor-usage assays. Moreover, there was no apparent outgrowth of X4-only virus in the CC2/86-infected implants of SCH-C-treated mice. We obtained nearly identical results from a second SCID-hu cohort treated in the same fashion.
Conclusions: SCH-C has potent antiviral activity against CC1/85 (R5) and no activity against CC2/86 (R5X4) in SCID-hu Thy/Liv mice. There was no evidence for development of resistance to SCH-C or of outgrowth of X4-only virus in treated mice. CCR5 antagonists such as SCH-C continue to be promising new candidates for therapeutic intervention of HIV-1 infection.