HIV Genetic Diversity and Viral Neuropathogenesis

HIV遗传多样性和病毒神经发病机制

• 批准号: 8257050
• 负责人: GEORGETTE D. KANMOGNE
• 金额: $ 69.66万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 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/8257050
• 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

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. PUBLIC HEALTH RELEVANCE: Over 70% of the 33.4 million people currently living with HIV/AIDS are in sub-Saharan Africa and are infected with non-B HIV subtypes, including the recombinant HIV-1 CRF02_AG, which is spreading to other parts of the world, including America and Europe. This proposal investigates whether infection with HIV strains that have particular genetic characteristics, such as recombinant CRF02_AG, increases viral replication, cellular toxicity, and neurocognitive impairment. These novel studies will help unravel the role genetic variation plays in infection, transmission, and viral neuropathogenesis, and is relevant in tracking HIV/AIDS epidemiology and designing HAND therapeutic approaches.

描述（由申请人提供）：在联合抗逆转录病毒治疗（ART）时代，尽管HIV抑制和免疫重建增强，HIV相关神经认知障碍（HAND）仍然保持高患病率。大多数HAND研究都是在发达国家对感染艾滋病毒1亚型b的患者进行的。然而，在3340万艾滋病毒/艾滋病患者中，三分之二生活在撒哈拉以南非洲（SSA），他们感染了包括重组病毒在内的非乙型艾滋病毒亚型。喀麦隆及西非和中非附近地区的艾滋病毒流行的特点是艾滋病毒-1进化支具有广泛的多样性，并且出现了结合进化支a和G （CRF02_AG）的循环重组形式。HIV-1 CRF02_AG毒株是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，这种花叶病毒正在向世界其他地区传播，现在出现在欧洲、亚洲和美洲，但对其中枢神经系统的影响和神经发病机制一无所知。考虑到艾滋病的流行和艾滋病毒亚型的全球地理分布，病毒的遗传多样性可能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、传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，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比其父本亚型A、G和西方HIV-1亚型b的体外复制能力增强。由于Tat的主要作用是反激活病毒基因启动子并诱导转录，因此Tat很可能在CRF02_AG分离株的体外复制能力增强中起主要作用。我们进一步发现，HIV-1 CRF02_AG Tat氨基酸（AA）序列形成一个单系簇，与其他HIV-1亚型的Tat序列不同。因此，我们假设CRF02_AG与B亚型病毒相比具有更高的适应度，这增加了其细胞致病性、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。我们建议用三个具体目标来检验这些假设。目标1：在喀麦隆艾滋病毒感染者和艾滋病毒阳性患者中使用一系列神经心理学（NP）测试来制定规范。目的2：研究HIV基因型对病毒适应度和宿主对HAND易感性的影响。目的3：验证我们的假设，即CRF02_AG和B型Tat AA之间的差异影响Tat的转激活和毒性。这些新研究意义重大，将有助于确定HIV遗传变异对病毒适应性、Tat转激活和神经发病机制的影响。所产生的数据将有助于深入了解HIV遗传学、流行病学和HAND之间的联系。