DNA deaminases and HIV drug resistance

DNA 脱氨酶和 HIV 耐药性

• 批准号: 8644796
• 负责人: Eric Refsland
• 金额: $ 1.05万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2014-07-25
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8644796
• 关键词: AIDS/HIV problem; Address; Adverse effects; Affect; Anti-Retroviral Agents; Antiviral Agents; Cell Line; Characteristics; Chemicals; Complementary DNA; Consensus; Cytosine; Cytosine deaminase; DNA; DNA-Directed DNA Polymerase; Data; Deaminase; Deamination; Dependency; Development; Drug resistance; Drug user; Enzymes; Exhibits; Family; Family member; Figs - dietary; Future; Genes; Genetic Variation; HIV; HIV drug resistance; Host Defense; Human; Immune; Individual; Lead; Mediating; Mutagenesis; Mutation; Patients; Pharmaceutical Preparations; Phenotype; Population; Populations at Risk; Proteins; RNA-Directed DNA Polymerase; Relative (related person); Resistance; Reverse Transcription; Risk; Role; Source; T-Lymphocyte; Technology; Testing; Transcript; Treatment Protocols; Uracil; Viral; Viral Drug Resistance; Viral Proteins; Virus; Virus Diseases; Work; apolipoprotein B mRNA editing enzyme; base; drug resistant virus; effective therapy; in vivo; intravenous drug user; member; next generation sequencing; novel; novel therapeutics; polypeptide; public health relevance; substance abuser; therapy development; transition mutation; viral DNA; virus genetics

DESCRIPTION (provided by applicant): HIV lacking Vif is susceptible to human APOBEC3 (A3)-mediated restriction, rendering the virus non-infectious. The archetypal family member, A3G, has a well-defined role in HIV restriction in T cells. Other A3s have been implicated but despite nearly a decade of study, no consensus has been reached regarding the restrictive repertoire. Following reverse transcription, nascent viral cDNA transcripts are deaminated by A3 proteins resulting in transition mutations that inhibit HIV replication. To counteract this, Vif targets A3s for proteolytic degradation. However, sequences derived from infected patients exhibit G-to-A hypermutation, a hallmark of A3 activity, suggesting Vif neutralization in vivo is incomplete. I hypothesize that these mutations promote HIV genetic variation and underlie beneficial phenotypes such as the acquisition of drug resistance. In the following proposal, I will define three vital characteristics of the A3 family: (i) which A3s are relevant to HIV restriction,(ii) the extent to which they contribute to the HIV mutation rate, and, (iii) whether drug-resistant virl isolates emerge following A3-mediated sub-lethal mutagenesis. I anticipate that when taken together these studies will supply definitive conclusions to the innate host-defense field while prioritizing efforts to develop future HIV/AIDS therapies especially for HIV infected substance abusers.

描述（由申请人提供）：缺乏 Vif 的 HIV 容易受到人类 APOBEC3 (A3) 介导的限制，从而使病毒不具有传染性。原型家族成员 A3G 在 T 细胞中的 HIV 限制中具有明确的作用。其他 A3 也受到牵连，但尽管进行了近十年的研究，但尚未就限制性曲目达成共识。逆转录后，新生病毒 cDNA 转录物被 A3 蛋白脱氨基，从而产生抑制 HIV 复制的过渡突变。为了抵消这个问题，Vif 以 A3 为目标进行蛋白水解降解。然而，来自感染患者的序列表现出 G 至 A 的超突变，这是 A3 活性的标志，表明体内 Vif 中和是不完全的。我假设这些突变促进了艾滋病毒的遗传变异，并成为有益表型的基础，例如耐药性的获得。在接下来的提案中，我将 定义 A3 家族的三个重要特征：(i) 哪些 A3 与 HIV 限制相关，(ii) 它们对 HIV 突变率的贡献程度，以及 (iii) A3 后是否出现耐药病毒分离株介导的亚致死诱变。我预计，这些研究综合起来将为先天宿主防御领域提供明确的结论，同时优先努力开发未来的艾滋病毒/艾滋病疗法，特别是针对艾滋病毒感染的药物滥用者。