Long Term Effects of Chronic HIV Infection on the Developing Brain

描述(由申请人提供)：这份R01申请建立在一项成功的R21资助的基础上，该资助检查了一群罗马尼亚青少年和年轻人，他们是长期的艾滋病毒幸存者，尽管经过十多年的有效治疗，仍然表现出神经心理障碍(约50%的受试者)。这项研究下一阶段的关键特征是，这些很久以前就被肠道外感染的青少年晚期和20岁出头的艾滋病毒+病例，我们有大量的纵向生物学和治疗信息，可能会经历大脑成熟的改变，可能会出现神经认知和社会认知后遗症。在1989年之前，罗马尼亚只有13例艾滋病病例报告给世界卫生组织，而到1990年底，报告了1168例，其中1094例是13岁以下的儿童。在这些机构中传播的艾滋病毒的基因特征显示，所有儿童都感染了艾滋病毒F1 SA#1分支：研究HAART中长期存活的HIV+患者的神经内科(NM)特征，并将它们与手部特征进行比较。我们将研究过去和现在的NM数据之间的关系，包括CD4计数、VL、HAART和与手相关的元素，如NP损害、日常功能、危险行为、治疗依从性和精神并发症。SA#2：研究儿童早期感染分支F的长期幸存者中与手部相关的病毒遗传因素。我们将在体外对患者病毒分离株的神经趋化潜力进行测序和测试，并从有手或不有手的受试者的脑脊液和PBMC中提取HIV DNA，在env(C2-V3)编码区识别保守的病毒遗传元件(脑签名序列)。我们在具有良好特征的罗马尼亚队列中进行的研究提供了一个独特的机会，可以在宿主免疫、病毒、治疗、共病因素和自幼感染艾滋病毒的年轻人之间建立预后相关性，这些年轻人通常在大脑发育的最早阶段被感染。随着这些人的成熟，了解神经认知障碍对他们未来行为的影响将是重要的。

DESCRIPTION (provided by applicant): This R01 application builds upon a successful R21 grant that examined a cohort of Romanian adolescents and young adults who are long-term HIV survivors and who, despite over a decade of effective treatment, still demonstrate neuropsychological impairments (approx. 50% of subjects). The key feature of the next stage of this study is that these late teens and early 20s HIV+ cases, who were parenterally infected a long time ago, and for whom we have extensive longitudinal biological and treatment information, may experience altered maturation of the brain, with possible neurocognitive and social cognition sequelae. Prior to 1989, only 13 AIDS cases from Romania had been reported to the WHO, while by the end of 1990, 1168 cases were reported, of which 1094 were in children less than 13 years of age. Genetic characterization of the HIV circulating in these institutions revealed that all the children were infected with HIV clade F1 SA#1: Study the neuromedical (NM) characteristics of a long-term surviving cohort of HIV+ patients on HAART and compare them to the HAND features. We will examine the relationship between past and present NM data, including CD4 counts, VL, HAART and HAND-associated elements like: NP impairment, daily functioning, risk behavior, treatment adherence and psychiatric comorbidities. SA#2: Study the viral genetic factors associated with HAND in long-term survivors infected with clade F since early childhood. We will sequence and test in vitro the neurotropic potential of patient viral isolates and identify conserved viral genetic elements ('brain signature sequences') in the env (C2-V3) coding region, from HIV DNA extracted from the CSF and PBMC of subjects with or without HAND. Our study in the well-characterized Romanian cohort offers a unique opportunity to make prognostic correlations between host immune, viral, treatment, comorbid factors, and HAND in young adults who are living with HIV since childhood, most often being infected during the earliest stages of brain development. As these individuals mature, it will be important to understand the implications of neurocognitive impairment on their future behaviors.