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：
8599489
负责人：
GEORGETTE D. KANMOGNE
金额：
$ 67.97万
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/8599489
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）：尽管艾滋病毒抑制和免疫重建有所增加，但在联合抗逆转录病毒治疗（ART）时代，艾滋病毒相关神经认知障碍（HAND）的患病率仍然很高。大多数 HAND 研究是在发达国家针对感染 HIV-1 B 亚型的患者进行的。然而，3340 万艾滋病毒/艾滋病感染者中的三分之二生活在撒哈拉以南非洲 (SSA)，并且感染了非-B HIV亚型，包括重组病毒。喀麦隆以及西非和中非附近地区的 HIV 流行的特点是 HIV-1 进化枝的广泛多样性以及结合进化枝 A 和 G 的循环重组形式 (CRF02_AG) 的出现。 HIV-1 CRF02_AG 毒株构成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，人口超过 4.56 亿。此外，这种花叶病毒正在传播到世界其他地区，目前存在于欧洲、亚洲和美洲，但对其中枢神经系统影响和神经发病机制尚不清楚。考虑到艾滋病的流行和艾滋病毒亚型的全球地理分布，病毒遗传多样性可能会影响其传播和神经发病机制；然而，HIV 基因型和重组 HIV 毒株对病毒传播、感染性和神经艾滋病的影响尚不清楚。我们的建议填补了这一重要的知识空白。我们的初步研究表明，与其亲代A和G亚型以及西方HIV-1 B亚型相比，HIV-1 CRF02_AG在人巨噬细胞和外周血单核细胞中的体外复制能力有所增强。因为Tat的主要作用是反式激活病毒基因启动子并诱导转录，Tat 很可能在 CRF02_AG 分离株复制增加中发挥主要作用。我们进一步表明，HIV-1 CRF02_AG Tat 氨基酸（AA）序列形成单系簇，并且与其他 HIV-1 亚型的 Tat 序列不同。因此，我们假设与 B 亚型病毒相比，CRF02_AG 的适应性有所增强，这会增加其细胞病变性、神经炎症和血脑屏障 (BBB) 损伤。我们进一步假设 HIV 基因型影响宿主对 HAND 的易感性和疾病进展。我们建议在三个具体目标中检验这些假设。目标 1：对 HIV 感染者和 HIV+ 喀麦隆人进行一系列神经心理学 (NP) 测试来制定规范。目标 2：研究 HIV 基因型对病毒适应性和宿主对 HAND 易感性的影响。目标 3：检验我们的假设，即 CRF02_AG 和 B 亚型 Tat AA 之间的差异影响 Tat 反式激活和毒性。这些新颖的研究意义重大，将有助于确定 HIV 遗传变异对病毒适应性、Tat 反式激活和神经发病机制的影响。生成的数据将深入了解 HIV 遗传学、流行病学和 HAND 之间的联系。