resistance to the ccr5 inhibitor 5p12-rantes requires a difficult evolution from ccr5 to cxcr4 coreceptor use抵抗ccr5抑制剂5 p12-rantes需要困难的进化从ccr5趋化因子受体cxcr4 coreceptor使用.pdfVIP

Resistance to the CCR5 Inhibitor 5P12-RANTES Requires a Difficult Evolution from CCR5 to CXCR4 Coreceptor Use 1 1 2 3 4 Rebecca Nedellec , Mia Coetzer , Michael M. Lederman , Robin E. Offord , Oliver Hartley , Donald E. Mosier1* 1 Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, United States of America, 2 Department of Medicine, Case Western Reserve University, University Hospitals/Case Medical Center, Cleveland, Ohio, United States of America, 3 Mintaka Foundation for Medical Research, Geneva, Switzerland, 4 Department of Structural Biology and Bioinformatics, University of Geneva, Geneva, Switzerland Abstract Viral resistance to small molecule allosteric inhibitors of CCR5 is well documented, and involves either selection of preexisting CXCR4-using HIV-1 variants or envelope sequence evolution to use inhibitor-bound CCR5 for entry. Resistance to macromolecular CCR5 inhibitors has been more difficult to demonstrate, although selection of CXCR4-using variants might be expected. We have compared the in vitro selection of HIV-1 CC1/85 variants resistant to either the small molecule inhibitor maraviroc (MVC) or the macromolecular inhibitor 5P12-RANTES. High level resistance to MVC was conferred by the same envelope mutations as previously reported after 16–18 weeks of selection by increasing levels of MVC. The MVC- resistant mutants were fully sensitive to inhibition by 5P12-RANTES. By contrast, only transient and low level resistance to 5P12-RANTES was achieved in three sequential selection experiments, and each resulted in a subsequent collapse of virus replication. A fourth round of selection by 5P12-RANTES led, after 36 weeks, to a ‘‘resis