Laboratory Branch, Division of HIV/AIDS Prevention, National Center for HIV, Hepatitis, STD, and Tuberculosis Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
J Virol. 2013 Aug;87(16):8952-61. doi: 10.1128/JVI.01204-13. Epub 2013 Jun 5.
Maraviroc (MVC) is a potent CCR5 coreceptor antagonist that is in clinical testing for daily oral pre-exposure prophylaxis (PrEP) for HIV prevention. We used a macaque model consisting of weekly SHIV162p3 exposures to evaluate the efficacy of oral MVC in preventing rectal SHIV transmission. MVC dosing was informed by the pharmacokinetic profile seen in blood and rectal tissues and consisted of a human-equivalent dose given 24 h before virus exposure, followed by a booster postexposure dose. In rectal secretions, MVC peaked at 24 h (10,242 ng/ml) with concentrations at 48 h that were about 40 times those required to block SHIV infection of peripheral blood mononuclear cells (PBMCs) in vitro. Median MVC concentrations in rectal tissues at 24 h (1,404 ng/g) were 30 and 10 times those achieved in vaginal or lymphoid tissues, respectively. MVC significantly reduced macrophage inflammatory protein 1β-induced CCR5 internalization in rectal mononuclear cells, an indication of efficient binding to CCR5 in rectal lymphocytes. The half-life of CCR5-bound MVC in PBMCs was 2.6 days. Despite this favorable profile, 5/6 treated macaques were infected during five rectal SHIV exposures as were 3/4 controls. MVC treatment was associated with a significant increase in the percentage of CD3(+)/CCR5(+) cells in blood. We show that high and durable MVC concentrations in rectal tissues are not sufficient to prevent SHIV infection in macaques. The increases in CD3(+)/CCR5(+) cells seen during MVC treatment point to unique immunological effects of CCR5 inhibition by MVC. The implications of these immunological effects on PrEP with MVC require further evaluation.
马拉维若（MVC）是一种强效的 CCR5 核心受体拮抗剂，目前正在进行临床试验，作为每日口服暴露前预防（PrEP）用于 HIV 预防。我们使用恒河猴模型，每周进行一次 SHIV162p3 暴露，以评估口服 MVC 预防直肠 SHIV 传播的效果。MVC 的剂量是根据血液和直肠组织中的药代动力学特征确定的，包括在病毒暴露前 24 小时给予与人等效剂量，随后在暴露后给予一剂增强剂。在直肠分泌物中，MVC 在 24 小时时达到峰值（10242ng/ml），48 小时时的浓度约为体外阻断 SHIV 感染外周血单核细胞（PBMC）所需浓度的 40 倍。24 小时时直肠组织中的 MVC 中位数浓度（1404ng/g）分别是阴道或淋巴组织中浓度的 30 倍和 10 倍。MVC 显著降低了直肠单核细胞中巨噬细胞炎症蛋白 1β诱导的 CCR5 内化，表明其在直肠淋巴细胞中与 CCR5 有效结合。PBMC 中 CCR5 结合的 MVC 半衰期为 2.6 天。尽管有这种有利的特征，但在五次直肠 SHIV 暴露中，有 5/6 接受治疗的恒河猴被感染，而对照组有 3/4 被感染。MVC 治疗与血液中 CD3(+) / CCR5(+)细胞的百分比显著增加有关。我们表明，直肠组织中高且持久的 MVC 浓度不足以预防恒河猴感染 SHIV。在 MVC 治疗期间观察到的 CD3(+) / CCR5(+)细胞的增加表明 MVC 对 CCR5 抑制具有独特的免疫作用。这些免疫作用对 MVC 进行 PrEP 的影响需要进一步评估。
