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: 8301750
• 负责人: Xiao-Fang Yu
• 金额: $ 31.24万
• 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 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8301750
• 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 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; Regression Analysis; Research; Research Design; Research Personnel; Resistance; Reverse Transcription; Southeastern Asia; Study Subject; T-Lymphocyte; Time; Variant; Viral; Viral Load result; abstracting; caucasian American; chemokine; chemokine receptor; cohort; design; effective intervention; experience; innovation; insight; macrophage; novel; progression marker; racial and ethnic; receptor; transmission process; vif Gene Products

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.

摘要

项目成果

Circulating coxsackievirus A16 identified as recombinant type A human enterovirus, China.

• DOI: 10.3201/eid1708.101719
• 发表时间: 2011-08
• 期刊: Emerging infectious diseases
• 影响因子: 11.8
• 作者: Zhao K;Han X;Wang G;Hu W;Zhang W;Yu XF
• 通讯作者: Yu XF

HIV-1 diversity, drug-resistant mutations, and viral evolution among high-risk individuals in phase II HIV vaccine trial sites in southern China.

• DOI: 10.1371/journal.pone.0068656
• 发表时间: 2013
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Qi H;Zhao K;Xu F;Zhang X;Zhang Z;Yang L;Li C;Liang X;Guo W;Chen S;Liu Z;Zhang W;Yu XF
• 通讯作者: Yu XF

Reduced APOBEC3H variant anti-viral activities are associated with altered RNA binding activities.

• DOI: 10.1371/journal.pone.0038771
• 发表时间: 2012
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Zhen A;Du J;Zhou X;Xiong Y;Yu XF
• 通讯作者: Yu XF