A Multi-Site Investigation into the Effect of HIV Clade on Neurocognitive Impairm

描述(申请人提供)：HIV-1是地球上遗传多样性最大的病原体之一。事实上，一些编码区，如包膜，在不同的支系之间可以有30%以上的遗传差异。B分支HIV-1感染对神经认知功能的影响在发达国家已经有了很好的描述；然而，关于非B分支感染对神经认知功能的影响仍然存在争议。这项拟议研究的主要目的是1)描述和比较居住在巴西、中国、印度、罗马尼亚和美国的感染CRF01_AE和B、C和F分支的人中发生的艾滋病毒相关神经认知障碍(HAND)的负担，以及2)评估亚型之间的神经毒力和嗜神经基因决定因素。尚未回答的重要研究问题包括：当按人口和亚型分析时，世界不同地区的患病率、性质和进程如何比较？哪些特定的病毒遗传特征与神经毒力和中枢神经系统(CNS)播种有关？ 目前的建议旨在通过以下方式系统地解决这些问题：1)通过在巴西(B和C分支)、中国(CRF01_AE和B和C分支)、印度(C分支)、罗马尼亚(F分支)和美国(B分支)先前建立的队列中使用标准化测量来测量手，从而确定艾滋病毒亚型对神经认知能力的不同影响，2)通过从血液中提取的艾滋病毒RNA和DNA生成基于群体的环境和TAT编码区的基于群体的序列，来确定在手部按亚型和通过研究人群保存的艾滋病毒RNA的病毒遗传基序，3)通过对从巴西、印度和美国的B或C分支感染者的配对血液和脑脊液样本中提取的HIV RNA的env和Tat编码区进行克隆测序，确定在B和C分支之间的CNS区划过程中保守的HIV RNA中的病毒遗传基序。比较感染不同艾滋病毒分支的人群之间的手部负担需要标准化的程序来测量人群内和人群之间的手部负担。对HIV神经发病和神经嗜性的分支特异性基因决定因素的调查需要：1)研究对象和来自研究参与者的生物样本的良好特征，2)神经认知功能测量的标准化，3)所有研究环境中高质量的HIV RNA测序能力，4)参与地点之间序列和研究数据的安全和可靠的数据管理和通信能力，以及5)最先进的基因类型分析的专业知识。我们小组在上述每一个领域都展示了经验。

DESCRIPTION (provided by applicant): HIV-1 is one of the most genetically diverse pathogens on earth. In fact, some coding regions, such as envelope, can have more than 30% genetic difference between clades. The neurocognitive effects of clade B HIV-1 infection have been well characterized in the developed world; however, there continues to be controversy surronding the effect of non-clade B infection on the neurocognitive functioning. The overarching aims of the proposed study is to 1) characterize and compare the burden of HIV associated neurocognitive disorders (HAND) occurring among individuals living in Brazil, China, India, Romania and the United States and infected with CRF01_AE and clades B, C and F, and 2) evaluate the neurovirulent and neurotropic genotypic determinants between subtypes. Important research questions that remain unanswered include: How do the prevalence, nature and course of HAND in various parts of the world compare when analyzed by population and subtype? What specific viral genetic characteristics are associated with neurovirulence and seeding of the central nervous system (CNS)? The current proposal is designed to systematically address these issues by: 1) determining the differential effect of HIV subtype on neurocognitive performance by measuring HAND using standardized measures in previously established cohorts in Brazil (clades B and C), China (CRF01_AE and clades B and C), India (clade C), Romania (clade F) and the United States (clade B), 2) determining viral genetic motifs from HIV RNA that are conserved during HAND by subtype and by study population by performing clade-typing of study participants by generating population based sequences of the env and tat coding regions from HIV RNA and DNA extracted from blood, and 3) determining viral genetic motifs from HIV RNA that are conserved during CNS compartmentalization between clades B and C by performing clonal sequencing of the env and tat coding regions from HIV RNA extracted from paired blood and CSF samples collected from participants with clade B or C infection in Brazil, India and the United States. The comparison of the burden of HAND between groups infected with different HIV clades requires standardized procedures for the measurement of HAND within and across populations. Investigations into clade-specific genotypic determinants of HIV neuropathogenesis and neurotropism requires: 1) well-characterized study populations and biologic samples from study participants, 2) standardization of measurements of neurocognitive functioning, 3) high quality HIV RNA sequencing capability in all research study settings, 4) secure and reliable data management and communication capabilities for sequence and study data between participating sites, and 5) expertise in state-of- the-art genotypic analysis. Our group has demonstrated experience in each of these areas.