塞尼西维罗克，一种新型的CCR5（R5）和CCR2拮抗剂，对R5嗜性HIV-2临床分离株显示出体外活性。
Cenicriviroc, a Novel CCR5 (R5) and CCR2 Antagonist, Shows In Vitro Activity against R5 Tropic HIV-2 Clinical Isolates.
作者信息
Visseaux Benoit, Charpentier Charlotte, Collin Gilles, Bertine Mélanie, Peytavin Gilles, Damond Florence, Matheron Sophie, Lefebvre Eric, Brun-Vézinet Françoise, Descamps Diane
机构信息
INSERM, IAME, UMR 1137, Paris, France; Univ Paris Diderot, IAME, UMR 1137, Sorbonne Paris Cité, Paris, France; AP-HP, Hôpital Bichat, Laboratoire de Virologie, Paris, France.
INSERM, IAME, UMR 1137, Paris, France; Univ Paris Diderot, IAME, UMR 1137, Sorbonne Paris Cité, Paris, France; AP-HP, Hôpital Bichat, Pharmacologie des antirétroviraux, Paris, France.
出版信息
PLoS One. 2015 Aug 6;10(8):e0134904. doi: 10.1371/journal.pone.0134904. eCollection 2015.
BACKGROUND
Maraviroc activity against HIV-2, a virus naturally resistant to different HIV-1 antiretroviral drugs, has been recently demonstrated. The aim of this study was to assess HIV-2 susceptibility to cenicriviroc, a novel, once-daily, dual CCR5 and CCR2 antagonist that has completed Phase 2b development in HIV-1 infection.
METHODS
Cenicriviroc phenotypic activity has been tested using a PBMC phenotypic susceptibility assay against four R5-, one X4- and one dual-tropic HIV-2 clinical primary isolates. All isolates were obtained by co-cultivation of PHA-activated PBMC from distinct HIV-2-infected CCR5-antagonist-naïve patients included in the French HIV-2 cohort and were previously tested for maraviroc susceptibility using the same protocol. HIV-2 tropism was determined by phenotypic assay using Ghost(3) cell lines.
RESULTS
Regarding the 4 R5 HIV-2 clinical isolates tested, effective concentration 50% EC50 for cenicriviroc were 0.03, 0.33, 0.45 and 0.98 nM, similar to those observed with maraviroc: 1.13, 0.58, 0.48 and 0.68 nM, respectively. Maximum percentages of inhibition (MPI) of cenicriviroc were 94, 94, 93 and 98%, similar to those observed with maraviroc (93, 90, 82, 100%, respectively). The dual- and X4-tropic HIV-2 strains were resistant to cenicriviroc with EC50 >1000 nM and MPI at 33% and 4%, respectively.
CONCLUSIONS
In this first study assessing HIV-2 susceptibility to cenicriviroc, we observed an in vitro activity against HIV-2 R5-tropic strains similar to that observed with maraviroc. Thus, cenicriviroc may offer a once-daily treatment opportunity in the limited therapeutic arsenal for HIV-2. Clinical studies are warranted.
背景
马拉维若对HIV-2具有活性，HIV-2是一种对不同HIV-1抗逆转录病毒药物天然耐药的病毒，这一点最近已得到证实。本研究的目的是评估西尼考韦（cenicriviroc）对HIV-2的敏感性，西尼考韦是一种新型的每日一次的CCR5和CCR2双重拮抗剂，已完成HIV-1感染的2b期开发。
方法
使用PBMC表型敏感性试验检测了西尼考韦对4株R5型、1株X4型和1株双嗜性HIV-2临床原始分离株的表型活性。所有分离株均通过将来自法国HIV-2队列中未使用过CCR5拮抗剂的不同HIV-2感染患者的PHA激活的PBMC进行共培养获得，并且之前使用相同方案检测过对马拉维若的敏感性。使用Ghost(3)细胞系通过表型试验确定HIV-2嗜性。
结果
对于所检测的4株R5型HIV-2临床分离株，西尼考韦的半数有效浓度（EC50）分别为0.03、0.33、0.45和0.98 nM，与马拉维若的结果相似，后者分别为1.13、0.58、0.48和0.68 nM。西尼考韦的最大抑制百分比（MPI）分别为94%、94%、93%和98%，与马拉维若的结果相似（分别为93%、90%、82%、100%）。双嗜性和X4嗜性HIV-2毒株对西尼考韦耐药，EC50>1000 nM，MPI分别为33%和4%。
结论
在这项评估HIV-2对西尼考韦敏感性的首次研究中，我们观察到其对HIV-2 R5嗜性毒株的体外活性与马拉维若相似。因此，西尼考韦可能为HIV-2有限的治疗手段提供每日一次的治疗机会。有必要开展临床研究。
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