Pathogenesis of CMV Retinitis

人类巨细胞病毒（HCMV）视网膜炎仍然是HIV/AIDS患者的一个重要眼科问题。在艾滋病相关HCMV视网膜进化过程中，介导视网膜感染和视网膜破坏的基本病理生理途径和机制的研究提出了三个具体目标。这些目的将使用一种临床相关的小鼠CMV （MCMV）视网膜炎模型，该模型是我们实验室新颖的，其中MCMV在视网膜下接种到患有小鼠逆转录病毒诱导的免疫缺陷综合征（MAIDS）的C57BL/6小鼠。第一个目的是确定是否定量穿孔素细胞毒性途径的丧失是一个更好的预测MCMV视网膜炎易感性的指标，而不是定量外周淋巴细胞的绝对数量。本研究的后续实验将集中于利用一种创新的人穿孔素mRNA RT-PCR检测方法，测量伴有或不伴有HCMV视网膜炎的HIV/AIDS患者的穿孔素细胞毒性途径。第二个目的是确定在maid期间穿孔素介导的细胞毒性被抑制的途径，从而导致MCMV视网膜炎的易感性。这些实验将重点关注白细胞介素-4，它在女仆调节过程中上调，并被认为将细胞毒性t细胞杀伤从主要的穿孔素途径转变为主要的Fas/FasL途径。第三个目的是确定肿瘤坏死因子-a （TNF-a）诱导的细胞凋亡在maids相关的MCMV视网膜炎中介导视网膜组织破坏的作用，特别关注未感染病毒的视网膜神经元。这些研究将为在逆转录病毒诱导的免疫抑制的独特环境中视网膜疾病进化过程中发生的病毒学、免疫学和发病事件提供新的见解，为开发新的诊断策略以更好地预测HIV/AIDS患者HCMV视网膜炎的发病提供信息，并为在临床环境中更好地管理这种威胁视力的疾病制定合理的治疗策略。

DESCRIPTION: Human cytomegalovirus (HCMV) retinitis remains a significant ophthalmologic problem in patients with HIV/AIDS. Three specific aims are proposed to continue study of the basic pathophysiologic pathways and mechanisms that mediate retinal infection and retinal destruction during evolution of AIDS-related HCMV retinal. These aims will use a clinically relevant mouse model of murine CMV (MCMV) retinitis novel to our laboratory in which MCMV is inoculated subretinally into C57BL/6 mice with MAIDS, a murine retrovirus-induced immunodeficiency syndrome. The first aim will determine if quantification of loss of the perforin cytotoxic pathway is a better predictor for susceptibility to MCMV retinitis than quantification of absolute numbers of peripheral lymphocytes during MAIDS progression. Subsequent experiments of this aim will focus on measurement of the perforin cytotoxic pathway in HIV/AIDS patients with or without HCMV retinitis using an innovative RT-PCR assay for human perforin mRNA. The second aim will determine the pathway by which perforin-mediated cytotoxicity is suppressed during MAIDS to allow susceptibility to MCMV retinitis. These experiments will focus on interleukin-4 which is upregulated during MAIDS and thought to shift cytotoxic T-cell killing from a dominant perforin pathway to a dominant Fas/FasL pathway. The third aim will determine the contribution of tumor necrosis factor-a (TNF-a)-induced apoptosis in mediating retinal tissue destruction during MAIDS-related MCMV retinitis with special attention to retinal neurons not infected with virus. The proposed studies will provide new insights into the virologic, immunologic, and pathogenetic events that operate during evolution of retinal disease in the unique setting of retrovirus-induced immuno-suppression, information needed to develop new diagnostic strategies to better predict onset of HCMV retinitis in HIV/AIDS patients and to develop rational therapeutic strategies to better manage this sight-threatening disease in the clinical setting.