A novel allele influencing HIV infection among injection drug users

摘要 注射吸毒仍然是艾滋病毒-1感染和传播的一个重要因素 全世界。目前，美国超过25%的艾滋病病例可归因于注射吸毒。 注射吸毒者的艾滋病毒感染在东南亚也是一个日益严重的问题。 东欧：在中国，注射吸毒者占HIV-1感染者的50%以上。广泛性 种群研究表明，宿主基因组编码的多态 趋化因子及其受体与HIV-1感染和疾病的改变有关 进步。然而，这些研究主要是在高加索和非洲进行的 美国人口。显然，在不同种族和民族中可能存在额外的遗传因素 可进一步影响艾滋病毒-1感染和/或疾病进展的人群。最近，我们 观察到胞苷脱氨酶天然完全缺失等位基因的高频率 中国南部研究人群中的载脂蛋白BEC3B(A3B)。我们发现那些 A3B缺失的纯合子对HIV-1感染的抵抗力显著高于 野生型A3B等位基因纯合者(优势比=3[95%可信区间 1.2-7.5])。此外，多元回归分析显示显著的正相关 在A3B表达和病毒载量设定值之间。A3B等APOBEC3胞苷脱氨酶 在人T淋巴细胞和巨噬细胞中高表达。这些酶可以 在逆转过程中通过诱导胞苷脱氨基(C到U)可能增加HIV-1的变异 转录，导致HIV-1基因组G-to-A突变。某些APOBEC3蛋白 也抑制HIV-1感染，HIV-1通过编码Vif开发了一种反防御 蛋白。令人惊讶的是，A3B是唯一可以使HIV-1基因组突变的胞苷脱氨酶 被HIV-1 VIF幸免。在本应用程序中，我们建议进一步表征 通过执行以下具体目标删除A3B：目的1.进一步评估A3B的效果 HIV-1感染的A3B纯合子缺失。我们将自然地检查这一点的影响 在血清阴性注射吸毒者中随着时间的推移发生HIV-1感染的缺失以确定 这一删除提供了对HIV-1感染的持久保护。我们还将研究更多 我们现有队列中的研究对象，以进一步证实缺失对HIV-1的影响 感染CRF08菌株。目的2.确定全纯合子A3B的疗效 删除感染不同亚型的HIV-1。我们将特别研究它对以下方面的影响 CRF01和CRF08在我们已建立的队列中的吸毒人群中的感染情况。这些研究将解决 A3B缺失对HIV-1感染的影响是否具有HIV-1毒株特异性的问题。 目的3.纵向观察A3B缺失等位基因对HIV-1的影响 疾病的发展。疾病进展标志物将在感染HIV-1的患者中进行比较 A3B缺失纯合子的个人和HIV-1感染者中 至少有一个完整的A3B基因。我们还将比较A3B基因缺失对 HIV-1向其他宿主基因多态的传播和疾病进展 因子，包括人类白细胞抗原等位基因、趋化因子和趋化因子受体。拟议的研究是 既有创新性又有重要意义，因为它利用了一组独特的主题来剖析 新宿主因素对HIV-1传播和疾病进展的影响。一位少校 优势是能够研究新生的病毒传播和疾病进展 从一开始就密切关注HIV-1感染的疫区。调查 在一个未被充分研究的群体中宿主遗传多态的研究 在高加索人和非裔美国人的类似研究中有丰富的经验 是另一个优势。这项研究应该对复杂的相互作用提供关键的见解 HIV-1传播中的病毒、宿主遗传和行为因素与发病机制之间的关系 可能为我们提供有关设计有效干预策略的关键信息。

Abstract Injection drug use continues to be an important factor in HIV-1 infection and transmission worldwide. Over 25% of AIDS cases in the US are currently attributable to injection drug use. HIV infection in injection drug users (IDUs) also represents a growing problem in southeast Asia and eastern Europe: In China, IDUs account for more than 50% of HIV-1 infections. Extensive population studies have demonstrated that polymorphisms in host genomes encoding chemokines and their receptors are associated with altered rates of HIV-1 infection and disease progression. However, these studies have mainly been conducted in Caucasian and African American populations. Clearly, additional genetic factors may exist in various racial and ethnic populations that can further affect HIV-1 infection and/or disease progression. Recently, we observed high frequencies of a natural complete deletion allele of the cytidine deaminase APOBEC3B (A3B) in our IDU study population in southern China. We found that people who are homozygous for the A3B deletion are significantly more resistant to HIV-1 infection than those who are homozygous for the wild-type A3B alleles (odds ratio=3 [95% confidence interval 1.2-7.5]). Furthermore, multiple regression analysis revealed significant positive associations between A3B expression and viral load set-points. APOBEC3 cytidine deaminases such as A3B are highly expressed in human T lymphocytes and macrophages. These enzymes can potentially increase HIV-1 variation by inducing cytidine deamination (C to U) during reverse transcription, resulting in G-to-A mutations in the HIV-1 genome. Certain APOBEC3 proteins also inhibit HIV-1 infection, and HIV-1 has developed a counter-defense by encoding the Vif protein. Amazingly, A3B is the only cytidine deaminase that can mutate the HIV-1 genome and be spared by HIV-1 Vif. In this application, we propose to further characterize the effects of the A3B deletion by carrying out the following specific aims: Aim 1. To further evaluate the effect of a homozygous deletion of A3B on HIV-1 infection. We will examine the effect of this naturally occurring deletion on HIV-1 infection over time among seronegative IDUs to determine whether the deletion confers persistent protection against HIV-1 infection. We will also examine more study subjects in our existing cohort to further substantiate the effect of the deletion on HIV-1 infection with the CRF08 strain. Aim 2. To determine the effect of a complete homozygous A3B deletion on infection with different HIV-1 subtypes. In particular, we will examine its effect on CRF01 and CRF08 infection among IDUs in our established cohorts. These studies will address the question of whether the effect of A3B deletion on HIV-1 infection is HIV-1 strain specific. Aim 3. To perform longitudinal observations on the effect of A3B deletion alleles on HIV-1 disease progression. The disease progression markers will be compared in HIV-1-infected individuals who are homozygous for the A3B deletion and in HIV-1-infected individuals who have at least one intact A3B gene. We will also compare the influence of the A3B deletion on HIV-1 transmission and disease progression to those of polyphorphisms in other host genetic factors, including HLA alleles, chemokines, and chemokine receptors. The proposed research is both innovative and significant in that it utilizes a unique population of subjects to dissect the influence of novel host factors on HIV-1 transmission and disease progression. A major advantage is the ability to study viral transmission and disease progression in a nascent epidemic area where HIV-1 infection has been closely followed from the beginning. Investigation of host genetic polymorphism in an understudied population by established researchers who have had extensive experience in similar types of studies in Caucasians and African Americans is a further advantage. This study should provide critical insights into the complex interplay between viral, host genetic, and behavioral factors in HIV-1 transmission and pathogenesis and may provide us with critical information regarding the design of effective intervention strategies.