Center for Comparative Medicine, University of California Davis, Davis, California, United States of America.
PLoS One. 2012;7(5):e37931. doi: 10.1371/journal.pone.0037931. Epub 2012 May 24.
Considerable evidence has accumulated that multiple viruses, bacteria, and protozoa manipulate interleukin-10 (IL-10)-mediated signaling through the IL-10 receptor (IL-10R) in ways that could enable establishment of a persistent microbial infection. This suggests that inhibition of pathogen targeting of IL-10/IL-10R signaling could prevent microbial persistence. Human cytomegalovirus (HCMV) and rhesus cytomegalovirus (RhCMV) express a viral interleukin-10 (cmvIL-10 and rhcmvIL-10, respectively) with comparable immune modulating properties in vitro to that of their host's cellular IL-10 (cIL-10). A prior study noted that rhcmvIL-10 alters innate and adaptive immunity to RhCMV in vivo, consistent with a central role for rhcmvIL-10 during acute virus-host interactions. Since cmvIL-10 and rhcmvIL-10 are extremely divergent from the cIL-10 of their respective hosts, vaccine-mediated neutralization of their function could inhibit establishment of viral persistence without inhibition of cIL-10.
As a prelude to evaluating cmvIL-10-based vaccines in humans, the rhesus macaque model of HCMV was used to interrogate peripheral and mucosal immune responses to rhcmvIL-10 in RhCMV-infected animals. ELISA were used to detect rhcmvIL-10-binding antibodies in plasma and saliva, and an IL-12-based bioassay was used to quantify plasma antibodies that neutralized rhcmvIL-10 function. rhcmvIL-10 is highly immunogenic during RhCMV infection, stimulating high avidity rhcmvIL-10-binding antibodies in the plasma of all infected animals. Most infected animals also exhibited plasma antibodies that partially neutralized rhcmvIL-10 function but did not cross-neutralize the function of rhesus cIL-10. Notably, minimally detectable rhcmvIL-10-binding antibodies were detected in saliva.
This study demonstrates that rhcmvIL-10, as a surrogate for cmvIL-10, is a viable vaccine candidate because (1) it is highly immunogenic during natural RhCMV infection, and (2) neutralizing antibodies to rhcmvIL-10 do not cross-react with rhesus cIL-10. Exceedingly low rhcmvIL-10 antibodies in saliva further suggest that the oral mucosa, which is critical in RhCMV natural history, is associated with suboptimal anti-rhcmvIL-10 antibody responses.
大量证据表明，多种病毒、细菌和原生动物通过白细胞介素-10（IL-10）受体（IL-10R）操纵 IL-10 介导的信号转导，从而能够建立持续的微生物感染。这表明抑制病原体对 IL-10/IL-10R 信号的靶向作用可能防止微生物的持续存在。人巨细胞病毒（HCMV）和恒河猴巨细胞病毒（RhCMV）分别表达病毒白细胞介素-10（cmvIL-10 和 rhcmvIL-10），其体外免疫调节特性与宿主细胞白细胞介素-10（cIL-10）相当。先前的研究表明，rhcmvIL-10 改变了 RhCMV 体内的先天和适应性免疫，这与 rhcmvIL-10 在急性病毒-宿主相互作用中的核心作用一致。由于 cmvIL-10 和 rhcmvIL-10 与其宿主的 cIL-10 极其不同，因此疫苗介导的其功能中和作用不会抑制 cIL-10 的功能而抑制病毒的持续存在。
作为在人体中评估 cmvIL-10 疫苗的前奏，使用恒河猴巨细胞病毒模型来研究 RhCMV 感染动物中 rhcmvIL-10 对周围和粘膜免疫的影响。ELISA 用于检测血浆和唾液中的 rhcmvIL-10 结合抗体，基于白细胞介素-12 的生物测定用于定量中和 rhcmvIL-10 功能的血浆抗体。在 RhCMV 感染期间，rhcmvIL-10 具有高度的免疫原性，刺激所有感染动物血浆中高亲和力的 rhcmvIL-10 结合抗体。大多数感染动物还表现出部分中和 rhcmvIL-10 功能的血浆抗体，但不交叉中和恒河猴 cIL-10 的功能。值得注意的是，在唾液中检测到最低限度可检测的 rhcmvIL-10 结合抗体。
这项研究表明，rhcmvIL-10 作为 cmvIL-10 的替代物，是一种可行的疫苗候选物，因为（1）它在天然 RhCMV 感染期间具有高度的免疫原性，（2）中和 rhcmvIL-10 的抗体与恒河猴 cIL-10 不发生交叉反应。唾液中极低的 rhcmvIL-10 抗体进一步表明，在 RhCMV 自然史中至关重要的口腔粘膜与亚最佳抗 rhcmvIL-10 抗体反应有关。
