{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T06:28:58Z","timestamp":1791181738884,"version":"4.1.0"},"reference-count":39,"publisher":"American Society for Microbiology","issue":"6","license":[{"start":{"date-parts":[[2013,6,1]],"date-time":"2013-06-01T00:00:00Z","timestamp":1370044800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2013,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>Small-molecule CCR5 antagonists, such as maraviroc (MVC), likely block HIV-1 through an allosteric, noncompetitive inhibition mechanism, whereas inhibition by agonists such as PSC-RANTES is less defined and may involve receptor removal by cell surface downregulation, competitive inhibition by occluding the HIV-1 envelope binding, and\/or allosteric effects by altering CCR5 conformation. We explored the inhibitory mechanisms of maraviroc and PSC-RANTES by employing pairs of virus clones with differential sensitivities to these inhibitors. Intrinsic PSC-RANTES-resistant virus (YA versus RT) or those selected in PSC-RANTES treated macaques (M584 versus P3-4) only displayed resistance in multiple-cycle assays or with a CCR5 mutant that cannot be downregulated. In single-cycle assays, these HIV-1 clones displayed equal sensitivity to PSC-RANTES inhibition, suggesting effective receptor downregulation. Prolonged PSC-RANTES exposure resulted in desensitization of the receptor to internalization such that increasing virus concentration (substrate) could saturate the receptors and overcome PSC-RANTES inhibition. In contrast, resistance to MVC was observed with the MVC-resistant HIV-1 (R3 versus S2) in both multiple- and single-cycle assays and with altered virus concentrations, which is indicative of allosteric inhibition. MVC could also mediate inhibition and possibly resistance through competitive mechanisms.<\/jats:p>","DOI":"10.1128\/aac.02511-12","type":"journal-article","created":{"date-parts":[[2013,3,26]],"date-time":"2013-03-26T00:15:56Z","timestamp":1364256956000},"page":"2640-2650","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":16,"title":["Multifaceted Mechanisms of HIV Inhibition and Resistance to CCR5 Inhibitors PSC-RANTES and Maraviroc"],"prefix":"10.1128","volume":"57","author":[{"given":"Michael A.","family":"Lobritz","sequence":"first","affiliation":[{"name":"Department of Molecular Biology and Microbiology, Case Western Reserve University, Cleveland, Ohio, USA"},{"name":"Division of Infectious Diseases, Department of Medicine, Case Western Reserve University, Cleveland, Ohio, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annette N.","family":"Ratcliff","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Microbiology, Case Western Reserve University, Cleveland, Ohio, USA"},{"name":"Division of Infectious Diseases, Department of Medicine, Case Western Reserve University, Cleveland, Ohio, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andre J.","family":"Marozsan","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Medicine, Case Western Reserve University, Cleveland, Ohio, USA"},{"name":"Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dawn M.","family":"Dudley","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Microbiology, Case Western Reserve University, Cleveland, Ohio, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John C.","family":"Tilton","sequence":"additional","affiliation":[{"name":"Center for Proteomics and Bioinformatics, Case Western Reserve University, Cleveland, Ohio, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric J.","family":"Arts","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Medicine, Case Western Reserve University, Cleveland, Ohio, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.virol.2006.01.018"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.77.9.5201-5208.2003"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.090576697"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.02006-06"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.virol.2006.11.004"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1097\/COH.0b013e3280142007"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0404802101"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.47.2.509-517.2003"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1099288"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.151.6.1281"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.187.8.1215"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.77.2.1610-1613.2003"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.75.18.8605-8614.2001"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.221375398"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.virol.2006.05.016"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.74.10.4868-4876.2000"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.02739-06"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M108232200"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00055-09"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01863-12"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1099\/0022-1317-36-1-59"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.71.10.7478-7487.1997"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01109-10"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.87.19.7787"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.2144\/000113119"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.78.20.11130-11141.2004"},{"key":"e_1_3_3_28_2","volume-title":"Proquest\/UMI","author":"Lobritz MA","year":"2007","unstructured":"LobritzMA. 2007. 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