Pathogenesis of CMV Retinitis

描述：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。提出了三个具体的目标，以继续研究在艾滋病相关的人巨细胞病毒视网膜演变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。这些目标将使用临床相关的小鼠巨细胞病毒(MCMV)视网膜炎的小鼠模型，在我们的实验室中，MCMV被接种到有MAILS的C57BL/6小鼠视网膜下，这是一种小鼠逆转录病毒诱导的免疫缺陷综合征。第一个目的将确定穿孔素细胞毒途径缺失的定量是否比定量外周淋巴细胞的绝对数更能预测MCMV视网膜炎的易感性。这一目标的后续实验将集中在使用一种创新的人穿孔素mRNA的RT-PCR方法来测量患有或不患有HCMV视网膜炎的HIV/AIDS患者的穿孔素细胞毒途径。第二个目标将确定穿孔素介导的细胞毒性在保姆期间被抑制的途径，以允许对MCMV视网膜炎的易感性。这些实验将聚焦于白介素4，它在女佣期间上调，被认为将细胞毒性T细胞杀伤从主要的穿孔素途径转移到主要的Fas/FasL途径。第三个目标将确定肿瘤坏死因子-a(TNF-a)诱导的细胞凋亡在MCMV相关性视网膜炎期间介导视网膜组织破坏中的作用，并特别关注未感染病毒的视网膜神经元。拟议的研究将为在逆转录病毒诱导的免疫抑制的独特环境下视网膜疾病的演变过程中操作的病毒学、免疫学和致病事件提供新的见解，为开发新的诊断策略以更好地预测艾滋病毒/艾滋病患者的HCMV视网膜炎的发病以及开发合理的治疗策略以在临床环境中更好地管理这种威胁视力的疾病提供所需的信息。

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.