Pathogenesis of CMV Retinitis

描述：人类巨细胞病毒（HCMV）视网膜炎仍然是一个重要的眼科问题，艾滋病毒/艾滋病患者。提出了三个具体的目标，继续研究艾滋病相关的HCMV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。这些目标将使用一个临床相关的小鼠模型，小鼠CMV（MCMV）视网膜炎的新的我们的实验室，其中MCMV视网膜下接种到C57 BL/6小鼠与MAIDS，小鼠逆转录病毒诱导的免疫缺陷综合征。第一个目的是确定在MAIDS进展期间，穿孔素细胞毒性途径的定量损失是否比外周淋巴细胞绝对数量的定量更好地预测MCMV视网膜炎的易感性。这一目标的后续实验将集中于使用针对人穿孔素mRNA的创新RT-PCR测定来测量有或没有HCMV视网膜炎的HIV/AIDS患者中的穿孔素细胞毒性途径。第二个目标将确定在MAIDS期间穿孔素介导的细胞毒性被抑制以允许对MCMV视网膜炎的易感性的途径。这些实验将集中在白细胞介素-4上，白细胞介素-4在MAIDS期间上调，并被认为将细胞毒性T细胞杀伤从主导穿孔素途径转移到主导Fas/FasL途径。 第三个目标是确定肿瘤坏死因子-α（TNF-α）诱导的细胞凋亡在MAIDS相关MCMV视网膜炎期间介导视网膜组织破坏中的作用，特别注意未感染病毒的视网膜神经元。拟议的研究将提供新的见解，病毒学，免疫学和致病事件，在视网膜疾病的演变过程中，在独特的逆转录病毒诱导的免疫抑制，信息需要开发新的诊断策略，以更好地预测发病的HCMV视网膜炎的艾滋病毒/艾滋病患者和开发合理的治疗策略，以更好地管理这种视力威胁疾病的临床环境。

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.