HIV Genetic Diversity and Viral Neuropathogenesis

描述（由申请人提供）：尽管HIV抑制和免疫重建增加，但在联合抗逆转录病毒治疗（ART）时代，HIV相关神经认知障碍（HAND）仍保持高患病率。大多数HAND研究是在发达国家对感染HIV-1亚型B的患者进行的。然而，3340万艾滋病毒/艾滋病感染者中有三分之二生活在撒哈拉以南非洲，感染了非B型艾滋病毒亚型，包括重组病毒。喀麦隆及西非和中非附近地区的艾滋病毒流行的特点是HIV-1进化枝的广泛多样性和出现了一种结合进化枝A和G的循环重组形式（CRF02_AG）。HIV-1 CRF02_AG株构成中非和西非的主要（52%至84%）病毒基因型，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一无所知。考虑到艾滋病的流行和HIV亚型的全球地理分布，病毒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。我们的初步研究显示，与亲本亚型A和G以及Western HIV-1亚型B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增加。由于达特的主要作用是反式激活病毒基因启动子并诱导转录，因此达特可能在CRF02_AG分离株的这种复制增加中起主要作用。我们进一步表明，HIV-1 CRF02_AG达特氨基酸（AA）序列形成一个单系簇，并不同于其他HIV-1亚型的达特序列。因此，我们假设CRF 02_AG与亚型B病毒相比具有增加的适应性，并且这增加了其细胞病变、神经炎症和血脑屏障（BB B）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测试这些假设。目的1：在HIV-和HIV+的喀麦隆人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：检验我们的假设，即CRF 02_AG和B亚型达特AA之间的差异影响达特反式激活和毒性。这些新的研究是有意义的，将有助于确定艾滋病病毒的遗传变异对病毒适应性，达特反式激活和神经发病机制的影响。产生的数据将提供深入了解艾滋病毒遗传学，流行病学和手之间的联系。 公共卫生相关性：目前，3340万艾滋病毒/艾滋病感染者中有70%以上生活在撒哈拉以南非洲，感染的是非B型艾滋病毒亚型，包括重组HIV-1 CRF02_AG，这种病毒正在向世界其他地区传播，包括美洲和欧洲。该提案调查了感染具有特定遗传特征的HIV毒株（如重组CRF02_AG）是否会增加病毒复制、细胞毒性和神经认知障碍。这些新的研究将有助于揭示遗传变异在感染、传播和病毒神经发病机制中的作用， 跟踪艾滋病毒/艾滋病流行病学和设计HAND治疗方法。

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.