Ketas Thomas J, Kuhmann Shawn E, Palmer Ashley, Zurita Juan, He Weijing, Ahuja Sunil K, Klasse Per Johan, Moore John P
Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY 10021, USA.
Virology. 2007 Aug 1;364(2):281-90. doi: 10.1016/j.virol.2007.02.022. Epub 2007 Apr 10.
Several CCR5 ligands, including small molecules and monoclonal antibodies (MAbs), are being developed as therapies for infection with strains of human immunodeficiency virus type 1 (HIV-1) that use CCR5 for entry (R5 viruses). The efficacy of such therapies could be influenced by inter-individual differences in host factors, such as CCR5 expression levels. To study this, we used peripheral blood mononuclear cells (PBMCs) from humans and rhesus macaques. The half-maximal inhibitory concentrations (IC(50)) of the small-molecule CCR5 ligands CMPD167, UK427,857 and SCH-D, and of the PRO 140 MAb, differ by >2 logs in a donor-dependent manner. We studied this variation by using flow cytometry to measure CCR5 expression on PBMCs from six of the human donors: the IC(50) values of both SCH-D and PRO 140 correlated with CCR5 expression (R(2)=0.64 and 0.99, respectively). We also determined the efficacy of the CCR5 ligands against HIV-1 infection of HeLa-derived cell lines that express CD4 at the same level but vary 2-fold in CCR5 expression (JC.48 and JC.53 cells). The moderately greater CCR5 expression on the JC.53 than the JC.48 cells was associated with proportionately higher median IC(50) values for all four CCR5 ligands but not for a soluble CD4-based inhibitor or a non-nucleoside reverse transcriptase inhibitor. We conclude that differences in CCR5 expression on human PBMCs, which can be affected by CCL3L1 gene dose, may influence the antiviral potency of CCR5 ligands in vitro, but other host factors are also likely to be involved. These host factors may affect the clinical activity of CCR5 inhibitors, including their use as topical microbicides to prevent HIV-1 transmission.
几种CCR5配体，包括小分子和单克隆抗体（MAb），正被开发用于治疗使用CCR5进入细胞的1型人类免疫缺陷病毒（HIV-1）毒株（R5病毒）感染。此类疗法的疗效可能受宿主因素个体差异的影响，如CCR5表达水平。为了研究这一点，我们使用了来自人类和恒河猴的外周血单个核细胞（PBMC）。小分子CCR5配体CMPD167、UK427857和SCH-D以及PRO 140单克隆抗体的半数最大抑制浓度（IC50）以依赖供体的方式相差超过2个对数级。我们通过流式细胞术测量来自6名人类供体的PBMC上的CCR5表达来研究这种差异：SCH-D和PRO 140的IC50值均与CCR5表达相关（R2分别为0.64和0.99）。我们还确定了CCR5配体对HeLa衍生细胞系HIV-1感染的疗效，这些细胞系表达相同水平的CD4，但CCR5表达相差2倍（JC.48和JC.53细胞）。JC.53细胞上CCR5表达略高于JC.48细胞，这与所有四种CCR5配体的中位IC50值相应更高有关，但与基于可溶性CD4的抑制剂或非核苷类逆转录酶抑制剂无关。我们得出结论，人类PBMC上CCR5表达的差异（可能受CCL3L1基因剂量影响）可能在体外影响CCR5配体的抗病毒效力，但其他宿主因素也可能参与其中。这些宿主因素可能影响CCR5抑制剂的临床活性，包括其作为局部杀菌剂预防HIV-1传播的用途。
