A novel allele influencing HIV infection among injection drug users

摘要 注射吸毒仍然是HIV-1感染和传播的重要因素 国际吧目前，美国超过25%的艾滋病病例是由于注射毒品。 在东南亚，注射吸毒者感染艾滋病毒也是一个日益严重的问题 在中国，注射吸毒者占HIV-1感染者的50%以上。广泛 群体研究表明，宿主基因组中编码 趋化因子及其受体与HIV-1感染率和疾病发生率的改变有关 进展然而，这些研究主要是在高加索人和非洲人中进行的。 美国人口。显然，在不同的种族和民族中可能存在其他遗传因素。 可能进一步影响HIV-1感染和/或疾病进展的人群。最近我们 观察到胞苷脱氨酶的天然完全缺失等位基因的高频率 APOBEC 3B（A3 B）在我们中国南方IDU研究人群中的表达。我们发现那些 A3 B缺失纯合子的人对HIV-1感染的抵抗力显著高于 野生型A3 B等位基因纯合子（优势比=3 [95%置信区间 1.2-7.5]）。此外，多元回归分析显示， A3 B表达和病毒载量设定点之间的关系。APOBEC 3胞苷脱氨酶，如A3 B 在人T淋巴细胞和巨噬细胞中高度表达。这些酶可以 通过在逆转录过程中诱导胞苷脱氨基（C至U），可能增加HIV-1变异 转录，导致HIV-1基因组中的G到A突变。某些APOBEC 3蛋白 也抑制HIV-1感染，HIV-1已经通过编码Vif开发了一种反防御， 蛋白令人惊讶的是，A3 B是唯一可以使HIV-1基因组突变的胞苷脱氨酶， 不会被HIV-1病毒感染在本申请中，我们提出进一步表征 A3 B删除，具体目标如下：为了进一步评估 HIV-1感染中A3 B的纯合缺失。我们自然会研究这方面的影响 随着时间的推移，在血清反应阴性的注射吸毒者中发生HIV-1感染缺失，以确定是否 该缺失赋予针对HIV-1感染的持久保护。我们也会研究更多 在我们现有的队列中研究受试者，以进一步证实删除对HIV-1的影响 感染CRF 08菌株。目标二。为了确定完全纯合子A3 B 在感染不同HIV-1亚型时的缺失。特别是，我们将研究其对 我们建立的队列中注射吸毒者的CRF 01和CRF 08感染。这些研究将解决 A3 B缺失对HIV-1感染的影响是否具有HIV-1株特异性的问题。 目标3。纵向观察A3 B缺失等位基因对HIV-1的影响 疾病进展。疾病进展标志物将在HIV-1感染者中进行比较。 A3 B缺失纯合子个体和 至少有一个完整的A3 B基因。我们还将比较A3 B缺失对 HIV-1传播和疾病进展到其他宿主遗传多态性 因子，包括HLA等位基因、趋化因子和趋化因子受体。拟议的研究是 这两个创新和重要的是，它利用了一个独特的人口的主题，剖析 新宿主因素对HIV-1传播和疾病进展的影响。一个主要 优势是能够研究病毒传播和疾病进展的新生 从一开始就密切关注HIV-1感染的流行地区。调查 在未充分研究的人群中， 在高加索人和非裔美国人的类似研究中具有丰富的经验 是另一个优点。这项研究应该为复杂的相互作用提供重要的见解 HIV-1传播和发病机制中的病毒、宿主遗传和行为因素之间的关系， 可以为我们提供关于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.