A novel allele influencing HIV infection among injection drug users

影响注射吸毒者艾滋病毒感染的新型等位基因

• 批准号: 7595964
• 负责人: Xiao-Fang Yu
• 金额: $ 34.05万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-30 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7595964
• 关键词: AIDS/HIV problem; Accounting; Acquired Immunodeficiency Syndrome; Address; Affect; African American; Alleles; Area; Behavioral Genetics; Caucasians; Caucasoid Race; China; Complex; Confidence Intervals; Cytidine; Cytidine Deaminase; Deamination; Disease Progression; Drug usage; Eastern Europe; Enzymes; Epidemic; Frequencies; Genes; Genetic; Genetic Polymorphism; Genome; HIV; HIV Infections; HIV-1; Human; Individual; Infection; Injecting drug user; Injection of therapeutic agent; Integration Host Factors; Intervention; Investigation; Lead; Mutate; Mutation; Odds Ratio; Pathogenesis; Population; Population Study; Proteins; Public Health; Rate; Regression Analysis; Research; Research Design; Research Personnel; Resistance; Reverse Transcription; Southeastern Asia; Study Subject; T-Lymphocyte; Time; Variant; Viral; Viral Load result; chemokine; chemokine receptor; cohort; design; experience; innovation; insight; macrophage; novel; racial and ethnic; receptor; transmission process; vif Gene Products

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.

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% 的艾滋病病例可归因于注射吸毒。注射吸毒者 (IDU) 感染艾滋病毒在东南亚和东欧也是一个日益严重的问题：在中国，注射吸毒者占 HIV-1 感染的 50% 以上。广泛的人群研究表明，编码趋化因子及其受体的宿主基因组中的多态性与 HIV-1 感染和疾病发生率的改变有关 进展。然而，这些研究主要是在白种人和非洲人中进行的 美国人口。显然，不同种族和民族中可能存在其他遗传因素 可以进一步影响 HIV-1 感染和/或疾病进展的人群。最近，我们 我们在中国南方的 IDU 研究人群中观察到胞苷脱氨酶 APOBEC3B (A3B) 的自然完全缺失等位基因的频率较高。我们发现，A3B 缺失纯合的人比野生型 A3B 等位基因纯合的人对 HIV-1 感染的抵抗力明显更高（比值比 = 3 [95% 置信区间 1.2-7.5]）。此外，多元回归分析显示 A3B 表达与病毒载量设定点之间存在显着正相关。 APOBEC3 胞苷脱氨酶（例如 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（C 到 U）来增加 HIV-1 变异，从而导致 HIV-1 基因组中的 G 到 A 突变。某些 APOBEC3 蛋白也能抑制 HIV-1 感染，而 HIV-1 通过编码 Vif 蛋白形成了一种反防御机制。令人惊讶的是，A3B 是唯一一种可以突变 HIV-1 基因组且不受 HIV-1 Vif 影响的胞苷脱氨酶。在本申请中，我们建议通过实现以下具体目标来进一步表征 A3B 缺失的影响： 目标 1. 进一步评估 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血清阴性注射吸毒者中 HIV-1 感染随时间的影响，以确定这种缺失是否能提供针对 HIV-1 感染的持久保护。我们还将检查现有队列中的更多研究对象，以进一步证实删除对 CRF08 毒株感染 HIV-1 的影响。目标 2. 确定完全纯合 A3B 缺失对不同 HIV-1 亚型感染的影响。特别是，我们将在已建立的队列中检查其对 IDU 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 缺失纯合的 HIV-1 感染者和至少具有一个完整 A3B 基因的 HIV-1 感染者中比较疾病进展标记。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素（包括 HLA 等位基因、趋化因子和趋化因子受体）多态性的影响。拟议的研究既具有创新性又意义重大，因为它利用独特的受试者群体来剖析新型宿主因素对 HIV-1 传播和疾病进展的影响。一个主要优势是能够研究新兴流行地区的病毒传播和疾病进展，从一开始就密切关注 HIV-1 感染情况。由在白人和非裔美国人的类似类型研究中拥有丰富经验的知名研究人员对未受研究人群中的宿主遗传多态性进行调查是另一个优势。这项研究应该为 HIV-1 传播和发病机制中病毒、宿主遗传和行为因素之间复杂的相互作用提供重要见解，并可能为我们提供有关设计有效干预策略的重要信息。公共卫生相关性：广泛的人群研究表明，编码趋化因子及其受体的宿主基因组中的多态性与 HIV-1 感染率和疾病进展的改变有关。然而，这些研究主要是在白人和非裔美国人群体中进行的。显然，不同种族和民族人群中可能存在其他遗传因素，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种可能影响 HIV-1 感染的新等位基因。了解宿主基因为何会影响 HIV-1 感染和疾病进展可能会带来 HIV/AIDS 的新治疗方法。