HIV Genetic Diversity and Viral Neuropathogenesis

HIV遗传多样性和病毒神经发病机制

基本信息

批准号：
8426089
负责人：
GEORGETTE D. KANMOGNE
金额：
$ 63.98万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-02-14 至 2016-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8426089
关键词：
AIDS Dementia Complex AIDS neuropathy AIDS/HIV problem Accounting Acquired Immunodeficiency Syndrome Affect Africa Africa South of the Sahara African Americas Amino Acid Sequence Amino Acids Area Asia Blood - brain barrier anatomy CCL2 gene Cameroon Central Africa Characteristics Country Data Developed Countries Disease Disease Progression Epidemic Epidemiology Europe Evaluation Feasibility Studies Gagging Genes Genetic Genetic Transcription Genetic Variation Genotype Geographic Distribution HIV HIV Infections HIV-1 High Prevalence Human IL8 gene Immunosuppression Impaired cognition Impairment In Vitro Individual Infection Inflammation Inflammatory Injury Interleukin-6 Knowledge Language Life Link Medical History Methods Modeling Mosaic Viruses Neurocognitive Neuropathogenesis Neuropsychological Tests Patients Peripheral Blood Mononuclear Cell Play Predisposition Prevalence Protein Sequence Analysis Proteins Recombinants Research Risk Role Sequence Analysis Serum Study Section Testing Therapeutic Tight Junctions Toxic effect Transactivation Viral Viral Genes Viral Proteins Virus antiretroviral therapy cytokine design fitness genetic epidemiology insight macrophage monocyte neuroinflammation neuropsychological novel pandemic disease promoter recombinant virus reconstitution tat Genes transmission process virus genetics

项目摘要

DESCRIPTION (provided by applicant): HIV-associated neurocognitive disorders (HAND) have persisted at a high prevalence in the era of combined antiretroviral therapy (ART) in spite of increased HIV suppression and immune reconstitution. The majority of HAND studies have been performed in developed countries on patients infected with HIV-1 subtype B. However, two-thirds of the 33.4 million people living with HIV/AIDS are in sub-Saharan Africa (SSA) and are infected with non-B HIV subtypes, including recombinant viruses. The HIV epidemic in Cameroon and nearby areas of West and Central Africa is characterized by both a broad diversity of HIV-1 clades and the emergence of a circulating recombinant form that combines clades A and G (CRF02_AG). The HIV-1 CRF02_AG strain constitutes the predominant (52 to 84%) viral genotype in Central and West Africa, a region that includes 26 countries with over 456 million inhabitants. Furthermore, this mosaic virus is spreading to other parts of the world and is now present in Europe, Asia, and America, but nothing is known of its CNS effects and neuropathogenesis. Considering the AIDS pandemic and global geographic distribution of HIV subtypes, it is possible that viral genetic diversity influences its spread and neuropathogenesis; however, the effects of HIV genotypes and recombinant HIV strains on viral transmission, infectivity, and neuroAIDS are not known. Our proposal fills this important knowledge gap. Our preliminary studies showed increased in vitro replication capacity of HIV-1 CRF02_AG in human macrophages and peripheral blood mononuclear cells, compared to its parental subtypes A and G and Western HIV-1 subtype B. Because the primary role of Tat is to transactivate viral gene promoter and induce transcription, it is likely that Tat play a major role in this increased replication of CRF02_AG isolates. We further show that HIV-1 CRF02_AG Tat amino acid (AA) sequences form a monophyletic cluster and are different from Tat sequences of other HIV-1 subtypes. Thus, we hypothesize that CRF02_AG has increased fitness compared to subtype B virus, and this increases its cytopathicity, neuroinflammation and blood-brain barrier (BBB) injury. We further hypothesize that HIV genotypes influence the host's susceptibility to HAND and disease progression. We propose to test these hypotheses in three specific aims. Aim 1: Use a battery of neuropsychological (NP) tests in HIV- and HIV+ Cameroonians to develop norms. Aim 2: Investigate the effects of HIV genotypes on viral fitness and the host's susceptibility to HAND. Aim 3: To test our hypothesis that differences between CRF02_AG and subtype B Tat AA influence Tat transactivation and toxicity. These novel studies are significant and will help determine the effect of HIV genetic variation on viral fitness, Tat transactivation and neuropathogenesis. Data generated will provide insights into the link between HIV genetics, epidemiology, and HAND.

描述（由申请人提供）：尽管HIV抑制和免疫结构增加了，但在联合抗逆转录病毒疗法（ART）的时代，与HIV相关的神经认知障碍（手）持续了很高的患病率。大多数手动研究是在发达国家对感染了HIV-1亚型的患者进行的。但是，在撒哈拉以南非洲（SSA）的3340万人中，有三分之二三分之二在撒哈拉以南非洲（SSA）中，并感染了非B HIV亚型，包括重组病毒在内。喀麦隆和西非西部和中部附近地区的艾滋病毒流行的特征是HIV-1进化枝的多样性以及结合了进化枝A和G（CRF02_AG）的循环重组形式的出现（CRF02_AG）。 HIV-1 CRF02_AG菌株构成了中非和西非的主要病毒基因型（52％至84％），该地区包括26个国家，其中超过4.56亿居民。此外，这种马赛克病毒正在传播到世界其他地区，现在存在于欧洲，亚洲和美国，但对其中枢神经系统的作用和神经病的发生尚无。考虑到艾滋病毒亚型的艾滋病大流行和全球地理分布，病毒遗传多样性可能会影响其扩散和神经病的发生。然而，尚不清楚HIV基因型和重组HIV菌株对病毒传播，感染性和神经辅助的影响。我们的建议填补了这一重要的知识差距。我们的初步研究表明，与其父母的亚型A和G型A和GIV-1亚型相比，HIV-1 CRF02_AG在人类巨噬细胞和外周血单核细胞中的体外复制能力增加。我们进一步表明，HIV-1 CRF02_AG TAT氨基酸（AA）序列形成单属群集，与其他HIV-1亚型的TAT序列不同。因此，我们假设与亚型B病毒相比，CRF02_AG具有提高的适应性，这增加了其细胞病变，神经炎症和血脑屏障（BBB）损伤。我们进一步假设HIV基因型会影响宿主对手和疾病进展的敏感性。我们建议以三个特定目标来检验这些假设。目标1：在HIV和HIV+喀麦隆人中使用一系列神经心理学（NP）测试来制定规范。 AIM 2：研究HIV基因型对病毒适应性的影响和宿主对手的敏感性。目的3：测试我们的假设，即CRF02_AG和亚型B tat aA之间的差异影响TAT的反式激活和毒性。这些新的研究很重要，将有助于确定HIV遗传变异对病毒适应性，TAT反式激活和神经病发生的影响。生成的数据将提供有关HIV遗传学，流行病学和手之间联系的见解。