The push and pull of inflammation on HIV susceptibility: impact of host variation in CD101 and AXL

摘要 尽管高度有效的抗逆转录病毒治疗和暴露前预防措施对公共健康有重大影响 关于艾滋病毒-1大流行，基本问题仍然存在，即界定艾滋病毒风险的生物机制。 性感染HIV-1。值得注意的是，在解释了直接导致基因变异的原因后，没有解释为什么 修改艾滋病毒-1进入和复制(最重要的是CCR5Δ-32)，有记录的艾滋病毒高暴露个人- 1表现出不同的结果，从快速感染到对HIV-1的长期自然抵抗力 感染。更好地了解这些表型可能会导致新的干预措施来减少HIV-1 收购。我们以前发现了功能变体(错义/无义、非翻译区或剪接位点) 在宿主基因中，这些基因与异性获得的HIV-1感染的风险变化密切相关。值得注意的是， CD101中的遗传变异与HIV-1风险增加有最强的相关性，而AXL中的变异 大大降低了风险。这两个基因都被认为调节宿主的炎症反应。CD101 调节T细胞活化，并在多种免疫细胞上表达。我们最近报告说循环中的T细胞 具有这些CD101变体的捐赠者的细胞和单核细胞，与没有功能性CD101的捐赠者相比 变种，显示出更高的整体细胞活性，但某些艾滋病毒保护性干扰素的表达减少 受刺激的基因。相反，Axl是一种受体酪氨酸激酶，被认为通过髓系细胞发挥抑制作用 细胞免疫激活，可能是通过抑制Toll样受体介导的先天免疫反应。 我们的主要假设是，宿主在CD101和AXL基因类型上的变异有助于改变 炎症动态平衡，从而影响感染艾滋病毒-1的风险。具体地说，我们假设 CD101变异体通过增加HIV-1的丰度和活性而增加感染HIV-1的风险 敏感的T细胞，同时也损害了它们固有的抗病毒防御能力。相反，如果没有这些， AXL变异体可能通过减少炎症而增强，从而降低了HIV-1感染的风险。 我们建议从三个方面对我们的假设进行评估：在目标1中，我们使用来自一组基因组数据，该队列具有良好的 表征HIV-1获得性表型，以便在第二个高HIV风险非洲队列中复制AXL变异 平衡CD101变异对HIV-1易感性的影响。在目标2中，我们测试了流行病学和 通过量化CD101和AXL变异与 已有基因组数据的两个美国人群对HIV-1感染的易感性：一个包括 主要是与男性发生性关系的白人男性；第二个是在美国各地招募的不同种族的队列 整个美国。在目标3中，我们将分子技术应用于血液和生殖器粘膜样本，这些样本存档在一个独特的 将这些CD101和AXL变异体的存在与宿主炎症直接联系起来的Biospecimen存储库 机制和体外HIV-1易感性。

ABSTRACT Despite the significant public health impact of highly active antiretroviral therapy and pre-exposure prophylaxis on the HIV-1 pandemic, fundamental questions remain about the biological mechanisms that define the risk of sexually acquiring HIV-1. Notably, there is no explanation why, after accounting for genetic variants that directly modify HIV-1 entry and replication (foremost CCR5Δ-32), individuals with documented high exposure to HIV- 1 exhibit diverse outcomes ranging from rapid infection to prolonged natural resistance to HIV-1 infection. A better understanding of these phenotypes could lead to novel interventions to reduce HIV-1 acquisition. We previously identified functional variants (missense/nonsense, untranslated region, or splice site) in host genes that are strongly associated with altered risk of heterosexually acquired HIV-1 infection. Notably, genetic variants in CD101 had the strongest association with increased HIV-1 risk, while variants in AXL had substantially reduced risk. Both genes are thought to regulate host inflammatory responses. CD101 regulates T cell activation and is expressed on many immune cell types. We recently reported that circulating T cells and monocytes from donors with these CD101 variants, compared to donors without functional CD101 variants, show higher overall cellular activation, but with reduced expression of certain HIV-protective interferon stimulated genes. In contrast, AXL is a receptor tyrosine kinase thought to act through myeloid cells to inhibit cellular immune activation, possibly through inhibition of toll-like receptor-mediated innate immune responses. Our overarching hypothesis is that host variation in CD101 and AXL genotypes contributes to altered inflammatory homeostasis, thereby influencing the risk of HIV-1 infection. Specifically, we hypothesize that CD101 variants confer a higher risk of HIV-1 infection by increasing the abundance and activation of HIV-1 susceptible T cells, while also compromising their innate antiviral defenses. Conversely, the absence of these variants, possibly augmented by reduced inflammation conferred by AXL variants, lowers HIV-1 infection risk. We propose to evaluate our hypothesis in three aims: in Aim 1, we use genomic data from a cohort with well- characterized HIV-1 acquisition phenotypes to replicate in a second high HIV-risk African cohort that AXL variants balance the impact of CD101 variants on HIV-1 susceptibility. In Aim 2, we test the epidemiological and population generalizability of our hypothesis by quantifying the association of CD101 and AXL variation with susceptibility to HIV-1 infection in two US populations for which genomic data already exist: one that includes predominantly white men who have sex with men; and a second, ethnically diverse cohort recruited across the entire US. In Aim 3, we apply molecular techniques to blood and genital mucosal samples archived in a unique biospecimen repository to directly link the presence of these CD101 and AXL variants with host inflammatory mechanisms, and ex vivo HIV-1 susceptibility.