Determinants of HIV Dynamics and Variation

HIV动态和变异的决定因素

• 批准号: 8386823
• 负责人: José Orlando Maldonado-Ortiz
• 金额: $ 3.66万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8386823
• 关键词: Acquired Immunodeficiency Syndrome; Affect; Amino Acid Substitution; Anti-Retroviral Agents; Biological; Biological Assay; CD4 Positive T Lymphocytes; Cells; Chronic Disease; Clinical; Complex; DNA biosynthesis; Development; Dideoxynucleosides; Disease Progression; Doctor of Dental Surgery; Doctor of Philosophy; Drug resistance; Failure; Frequencies; Genetic Variation; Goals; HIV; HIV Infections; HIV-1; Highly Active Antiretroviral Therapy; Human; Individual; Life; Life Expectancy; Morbidity - disease rate; Multi-Drug Resistance; Mutagenesis; Mutation; Pharmaceutical Preparations; Pharmacotherapy; Population Dynamics; RNA-Directed DNA Polymerase; Regimen; Research; Resistance; Role; Students; T-Lymphocyte; Testing; Time; United States National Institutes of Health; Vaccines; Variant; Viral; Virus; Virus Diseases; antiretroviral therapy; fitness; improved; insight; macrophage; mortality; mutant; research study; resistance mutation; viral DNA

DESCRIPTION (provided by applicant): Approximately 30 million individuals have died of AIDS and 33 million are currently infected with human immunodeficiency virus type 1 (HIV-1) worldwide. Highly active antiretroviral therapy (HAART) is currently the best treatment for HIV infection. HAART has dramatically reduced the rate of HIV-1 and AIDS-related morbidity and mortality. However, drug administration may result in drug therapy failure, which is associated with drug resistance mutations. Drug resistance significantly limits the clinical benefit of antiretroviral treatment. I am a D.D.S./Ph.D. dual degree student and this NIH F30 application proposes research that will thoroughly investigate the biological relevance of the A62V amino acid substitution in HIV-1 reverse transcriptase (RT). The A62V mutation is a substitution observed in HIV-1 clinical isolates that is associated with multi-drug resistance but is known not to be a resistance-conferring mutation. My preliminary studies have discovered that A62V increases HIV-1 mutant frequency. This is the first observation that this residue can influence HIV-1 mutagenesis. In this application, I propose 2 specific aims. In Specific Aim 1, I will investigate a) the role of A62V on virus fitness compared to wt virus using dual competition assay and b) the role of A62V on the efficiency of HIV-1 viral DNA synthesis by real-time PCR. I will also investigate the impact of A62V on HIV-1 mutagenesis in primary T-cells and macrophages using a single cycle replication assay. In Specific Aim 2, I will examine A62V in the context of known multi-dideoxynucleoside resistance (MDR) mutations. In particular, I will thoroughly examine these HIV-1 RT variants for effects on viral fitness, for effects on the efficiency of viral DNA synthesis, and effects on HIV-1 mutagenesis. A better understand HIV-1 population dynamics in the context of antiretroviral therapy is important for predicting disease progression, the durability of antiretroviral drug regimens, and for providing insights into potential vaccine approaches.

描述（由申请人提供）：大约3000万人死于艾滋病，目前3,300万人感染了全球人类免疫缺陷病毒1型（HIV-1）。高度活跃的抗逆转录病毒疗法（HAART）目前是HIV感染的最佳治疗方法。 Haart大大降低了HIV-1和与AIDS相关的发病率和死亡率的速度。但是，药物给药可能导致药物治疗衰竭，这与耐药性突变有关。耐药性显着限制了抗逆转录病毒治疗的临床益处。我是D.D.S./ph.d。双学位学生和NIH F30的应用提出了研究，该研究将彻底研究HIV-1逆转录酶（RT）中A62V氨基酸取代的生物学相关性。 A62V突变是在HIV-1临床分离株中观察到的替代物，它与多药抗性有关，但众所周知不是抗药性的突变。我的初步研究发现A62V会增加HIV-1突变频率。这是该残基会影响HIV-1诱变的第一个观察。在此应用程序中，我提出了2个具体目标。在特定的目标1中，我将使用双竞争测定法和b）A）与WT病毒相比，A）A）A62V对病毒适应性的作用和b）A62V对实时PCR的HIV-1病毒DNA合成效率的作用。我还将使用单个循环复制测定法研究A62V对原代T细胞和巨噬细胞中HIV-1诱变的影响。在特定目标2中，我将在已知的多脱氧核苷耐药性（MDR）突变的背景下检查A62V。特别是，我将彻底检查这些HIV-1 RT变体对病毒适应性的影响，对病毒DNA合成效率的影响以及对HIV-1诱变的影响。在抗逆转录病毒疗法的背景下，更好地理解HIV-1种群动力学对于预测疾病进展，抗逆转录病毒药物方案的耐用性以及对潜在疫苗方法的见解很重要。