HIV Residual Replication and Drug Holidays

HIV 残留复制和药物假期

• 批准号: 7629037
• 负责人: Eric Lorenzo
• 金额: $ 38.22万
• 依托单位: PONCE SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7629037
• 关键词: Adverse effects; Aftercare; Benefits and Risks; Biological Assay; CD4 Positive T Lymphocytes; Cell Count; Cells; Chronic; Clinical; Cytopathology; DNA; Detection; Development; Drug usage; Economics; Failure; Genetic; Genetic Transcription; HIV; HIV-1; Half-Life; Highly Active Antiretroviral Therapy; Holidays; Individual; Infection; Interphase Cell; Interruption; Knowledge; Lead; Longevity; Measures; Methods; Morbidity - disease rate; Numbers; Outcome; Patients; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Plasma; Population; Production; Proviruses; Publishing; Rate; Recording of previous events; Reporting; Research Personnel; Residual state; Rest; Sampling; Sequence Analysis; Source; T-Lymphocyte; Therapeutic; Thinking; Viral; Viral Load result; Viremia; Virion; Virus; Work; antiretroviral therapy; cell type; cost; design; improved; in vivo; innovation; monocyte; mortality; peripheral blood; viral RNA

Combinations of Highly Active Antiretroviral Therapy (HAART) have dramatically decreased morbidity and mortality in HIV-infected individuals. Despite prolonged treatment, infectious HIV continues to replicate and reside latently in reservoirs, creating a major obstacle in HIV eradication. The majority of HIV-infected individuals that undergo therapy interruption because of severe side effects, and/or high costs, rapidly develop an increase in viral loads and a decrease in CD4+ T-cell counts. This viral rebound during therapy interruption is not clearly associated v/ith "the major reservoir", resting CD4+ T-cells. The ability of HIV-infected monocytes to avoid cytopathology and the inability of HAART to block viral replication in these cells as efficiently as in CD4+ T cells may permit a continuous production of HIV in monocytes in patients under suppressive HAART. This suggests that monocytes could be important reservoirs and contributors to residual replication. We hypothesize that residual replication is an important factor in viral rebound after treatment interruption and that monocytes are a major contributor to residual replication. We propose to isolate and compare the proviral DNA of active CD4+ T cells, resting CD4+ T cells and HIV-infected monocytes and compare them phylogenetically with the residual replication during suppressive HAART to determine the contribution of monocytes and other types of cells in residual replication. We will isolate and measure this ongoing replication by quantifying the 2-LTR DNA episomal circles before therapy interruption and correlate them with the degree and rate of plasma virus RNA of the viral rebound and decrease of CD4+ T-cells during therapy interruption. We also propose to phylogenetically compare the C2-V3 env sequence of the 2-LTR circles before treatment interruption with the C2-V3 env sequence of the plasma virus RNA in viral rebound to determine if viral rebound is at least in part a result of residual replication. The determination of the viral source that emerges during HAART interruption would help design more effective therapies and strategies against HIV. The results obtained from this proposed work will be useful to better understand both the causes and the sources of the failure that is frequently observed during treatment interruption in patients with a previous clinical history of successful HAART. In addition, this study could lead to a method to systematically evaluate some of the risks and benefits of therapy interruption in the individual patient.

高效抗逆转录病毒疗法（HAART）的组合显着降低了艾滋病毒感染者的发病率和死亡率。尽管治疗时间延长，但传染性艾滋病毒继续复制并潜伏在宿主中，成为根除艾滋病毒的主要障碍。由于严重的副作用和/或高成本而经历治疗中断的大多数HIV感染个体迅速发展为病毒载量增加和CD 4 + T细胞计数减少。在治疗中断期间的这种病毒反弹与“主要储库”静息CD 4 + T细胞没有明确关联。HIV感染的单核细胞避免细胞病理学的能力和HAART不能像在CD 4 + T细胞中那样有效地阻断这些细胞中的病毒复制，这可能允许在抑制性HAART下患者的单核细胞中持续产生HIV。这表明单核细胞可能是重要的储库， 对残余复制的贡献者。我们假设，残余复制是治疗中断后病毒反弹的一个重要因素，单核细胞是残余复制的主要贡献者。我们建议分离和比较活性CD 4 + T细胞、静息CD 4 + T细胞和HIV感染的单核细胞的前病毒DNA，并将它们与抑制性HAART期间的残余复制进行遗传学比较，以确定单核细胞和HIV感染的单核细胞的贡献。 其他类型的细胞进行残余复制。我们将通过在治疗中断前定量2-LTR DNA附加体环来分离和测量这种正在进行的复制，并将其与治疗中断期间病毒反弹和CD 4 + T细胞减少的血浆病毒RNA的程度和速率相关联。我们还建议对治疗中断前2-LTR环的C2-V3 env序列与病毒反弹中血浆病毒RNA的C2-V3 env序列进行遗传学比较，以确定病毒反弹是否至少部分是残留复制的结果。确定HAART中断期间出现的病毒来源将有助于设计更有效的抗HIV治疗和策略。从这项拟议的工作中获得的结果将有助于更好地了解原因和 失败的来源，这是经常观察到的治疗中断期间的患者成功的HAART既往临床史。此外，这项研究可能会导致一种方法，系统地评估个别患者治疗中断的一些风险和受益。