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

描述（由申请人提供）：HIV-1是地球上遗传多样性最高的病原体之一。事实上，一些编码区，如包膜，可以有超过30%的进化枝之间的遗传差异。进化枝B HIV-1感染对神经认知功能的影响在发达国家已得到很好的表征;然而，围绕非进化枝B感染对神经认知功能的影响仍存在争议。拟定研究的总体目的是1）表征和比较生活在巴西、中国、印度、罗马尼亚和美国并感染CRF 01_AE和分支B、C和F的个体中发生的HIV相关神经认知障碍（HAND）的负担，2）评价亚型之间的神经毒性和嗜神经性基因型决定因素。重要的研究问题，仍然没有答案包括：如何在世界各地的流行率，性质和过程的手比较时，分析人口和亚型？哪些特定的病毒遗传特征与神经毒力和中枢神经系统（CNS）播种相关？ 本提案旨在通过以下方式系统地解决这些问题：1）通过在巴西先前建立的队列中使用标准化测量来测量HAND，确定HIV亚型对神经认知表现的不同影响（进化枝B和C），中国（CRF01_AE和进化枝B和C）、印度（进化枝C）、罗马尼亚（进化枝F）和美国（进化枝B），2）通过从血液提取的HIV RNA和DNA产生env和达特编码区的基于群体的序列，通过对研究参与者进行进化枝分型，通过亚型和研究群体确定在HAND期间保守的来自HIV RNA的病毒遗传基序，和3）通过对HIV RNA的env和达特编码区进行克隆测序，确定在进化枝B和C之间CNS区室化期间保守的HIV RNA的病毒遗传基序，所述HIV RNA提取自巴西、印度和美国的进化枝B或C感染的参与者的配对血液和CSF样品。不同HIV分支感染人群之间HAND负担的比较需要人群内和人群间HAND测量的标准化程序。对HIV神经发病机制和嗜神经性的进化枝特异性基因型决定因素的研究需要：1）来自研究参与者的良好表征的研究人群和生物样本，2）神经认知功能测量的标准化，3）所有研究环境中的高质量HIV RNA测序能力，4）参与地点之间的序列和研究数据的安全可靠的数据管理和通信能力，和5）最先进的基因型分析的专业知识。我们的团队在每个领域都有丰富的经验。

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.