A novel allele influencing HIV infection among injection drug users

描述（由申请人提供）：注射吸毒仍然是全球HIV-1感染和传播的一个重要因素。目前，美国超过25%的艾滋病病例是由于注射毒品。在东南亚和东欧，注射吸毒者（IDUs）感染HIV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。广泛的人群研究表明，宿主基因组中编码趋化因子及其受体的多态性与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 在中国南方的IDU研究人群中观察到高频率的胞苷脱氨酶APOBEC3B（A3B）天然完全缺失等位基因。我们发现，A3B缺失纯合子的人比野生型A3B等位基因纯合子的人对HIV-1感染的抵抗力更强（比值比= 3 [95%置信区间1.2 - 7.5]）。此外，多元回归分析显示A3B表达和病毒载量设定点之间存在显著正相关。APOBEC3胞苷脱氨酶如A3B在人T淋巴细胞和巨噬细胞中高度表达。这些酶可能通过在逆转录过程中诱导胞苷脱氨基（C至U）而增加HIV-1变异，导致HIV-1基因组中的G至A突变。某些APOBEC3蛋白也抑制HIV-1感染，HIV-1已经通过编码Vif蛋白开发了一种反防御。令人惊讶的是，A3B是唯一一种可以使HIV-1基因组突变而不被HIV-1 Vif破坏的胞苷脱氨酶。在本申请中，我们提出通过实施以下具体目标来进一步表征A3B缺失的影响：进一步评价A3B纯合缺失对HIV-1感染的影响。我们将研究这种自然发生的缺失对HIV-1感染的影响，随着时间的推移，血清阴性注射吸毒者，以确定是否删除赋予持久的保护对HIV-1感染。我们还将在现有队列中检查更多研究受试者，以进一步证实删除对CRF08株HIV-1感染的影响。目标二。确定完全纯合A3B缺失对不同HIV-1亚型感染的影响。特别是，我们将在我们建立的队列中检查其对注射吸毒者中CRF01和CRF08感染的影响。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。目标3：对A3B缺失等位基因对HIV-1疾病进展的影响进行纵向观察。将在A3B缺失纯合子的HIV-1感染个体和至少有一个完整A3B基因的HIV-1感染个体中比较疾病进展标志物。我们还将比较A3B缺失对HIV-1传播和疾病进展的影响与其他宿主遗传因子（包括HLA等位基因、趋化因子和趋化因子受体）中多态性的影响。这项研究具有创新性和重要性，因为它利用独特的受试者群体来剖析新的宿主因素对HIV-1传播和疾病进展的影响。一个主要的优势是能够在一个新生的流行地区研究病毒传播和疾病进展，在这个地区，HIV-1感染从一开始就受到密切关注。由在高加索人和非裔美国人的类似类型研究中具有丰富经验的知名研究人员在未充分研究的人群中调查宿主遗传多态性是进一步的优势。这项研究应该提供关键的见解病毒，宿主遗传和行为因素之间的复杂相互作用，在HIV-1的传播和发病机制，并可能为我们提供关键信息，设计有效的干预策略。公共卫生相关性：广泛的人群研究表明，宿主基因组中编码趋化因子及其受体的多态性与HIV-1感染率和疾病进展的改变有关。然而，这些研究主要在高加索人和非裔美国人人群中进行。显然，其他遗传因素可能存在于不同种族和民族人群中，这些因素可能进一步影响HIV-1感染和/或疾病进展。最近，我们在中国南方的IDU研究人群中观察到一个新的等位基因，可能会影响HIV-1感染。了解为什么宿主基因可以影响HIV-1感染和疾病进展可能会导致HIV/AIDS的新治疗方法。

DESCRIPTION (provided by applicant): 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 polymorphisms 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. PUBLIC HEALTH RELEVANCE: 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 a novel allele in our IDU study population in southern China that could influence HIV-1 infection. Understanding why host genes could influence HIV-1 infection and disease progression may lead to new treatments for HIV/AIDS.