VIROLOGIC & IMMUNOLOGIC STUDIES OF MURINE CMV RETINITIS

巨细胞病毒（CMV）视网膜炎是最常见的眼部机会性 艾滋病患者中观察到的感染和CMV视网膜炎的发展 取决于免疫缺陷。 在正常的非免疫抑制个体中， CMV通常是潜伏的，如果病毒重新激活， 病毒感染的细胞很快被宿主的免疫系统清除。 相反，在免疫抑制的宿主中，如艾滋病患者或 那些在器官移植后全身免疫功能低下的患者 移植，骨髓移植，或在化疗期间，CMV可以 引起全身和眼部表现的播散性疾病。 宿主无法对病毒产生有效的免疫反应， 病毒可能通过以下方式对这种疾病的发病机制起很大作用： 使病毒得以复制，全身和局部感染 CMV感染与免疫抑制有关。 在第一次融资期间 在此期间，我们证明了将5 × 10/2 PFU的MCMV接种到 免疫抑制的BALB/c小鼠（类固醇处理或T细胞耗尽）导致 在大多数（>90%）小鼠的暴发性视网膜坏死中。 病毒 在包括眼睛在内的几个部位变得潜伏， 通过免疫抑制重新激活。 在延迟期间，大多数 潜在感染的眼睛是阳性的转录MCMV立即 早期基因1（IE 1）。 MCMV视网膜炎的鼠模型将用于 本申请中提出的研究旨在：（1）确定是否 免疫抑制诱导的眼部潜伏MCMV再活化结果 来自眼部病毒的原位再活化，来自 再活化的病毒从眼外部位，或从组合原位 再活化病毒的再活化和血行播散，（2） 确定IE 1 mRNA的产生是否是MCMV潜伏期的标志物， 眼睛，和（3）确定是否过继转移NK细胞， 巨噬细胞和/或病毒特异性T细胞保护免受MCMV视网膜炎 在睫状体上接种之后。 研究结果，以确定 MCMV潜伏期的位点，并使用细胞方法预防MCMV 视网膜炎可能有助于我们了解CMV的致病机制 人类患者的视网膜炎。 实验结果，看看IE 1是否 转录物是小鼠眼睛中MCMV潜伏期的标志物， 可用于预测哪些CMV血清阳性的HIV-1感染患者 患CMV视网膜炎的风险最高

Cytomegalovirus (CMV) retinitis is the most common ocular opportunistic infection observed in patients with AIDS, and development of CMV retinitis depends on immunodeficiency. In normal, non-immunosuppressed individuals, CMV is usually latent, and if the virus does reactivate, presumably the virus-infected cells are quickly eliminated by the host's immune system. In contrast, in the immunosuppressed host, such as patients with AIDS or those patients who are systemically immunocompromised following an organ transplant, a bone marrow transplant, or during chemotherapy, CMV can cause disseminated disease with both systemic and ocular manifestations. The inability of the host to mount an effective immune response to the virus likely contributes much to the pathogenesis of this disease by allowing the virus to replicate, and both systemic and local infections with CMV are associated with immunosuppression. During the first funding period, we demonstrated that inoculation of 5 x 10/2 PFU of MCMV into immunosuppressed BALB/c mice (steroid-treated or T cell depleted) resulted in fulminant retinal necrosis in the majority (>90%) of the mice. Virus became latent at several sites, including the eye, and could be reactivated by immunosuppression. During latency, a majority of the latently-infected eyes were positive for transcripts of the MCMV immediate early gene 1 (IE1). The murine model of MCMV retinitis will be used in the studies proposed in this application to: (1) determine whether immunosuppression-induced reactivation of latent MCMV in the eye results from in situ reactivation of ocular virus, from hematogenous spread of reactivated virus from extraocular sites, or from a combination of in situ reactivation and hematogenous dissemination of reactivated virus, (2) determine whether production of IE1 mRNA is a marker for MCMV latency in the eye, and (3) determine whether adoptive transfer of NK cells, macrophages, and/or virus-specific T cells protects against MCMV retinitis following supraciliary inoculation. Results from studies to identify sites of MCMV latency and to use a cellular approach to prevent MCMV retinitis may help us understand the pathogenic mechanisms of CMV retinitis in human patients. Results of experiments to see whether IE1 transcripts are markers of MCMV latency in the mouse eye may ultimately be useful for predicting which CMV-seropositive, HIV-1 infected patients are at the highest risk of developing CMV retinitis.