HIV Residual Replication and Drug Holidays

HIV 残留复制和药物假期

• 批准号: 7475922
• 负责人: Eric Lorenzo
• 金额: $ 37.78万
• 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/7475922
• 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) 的联合治疗显着降低了 HIV 感染者的发病率和死亡率。尽管经过长期治疗，传染性艾滋病毒仍继续复制并潜伏在病毒库中，为根除艾滋病毒造成了重大障碍。大多数因严重副作用和/或高费用而中断治疗的 HIV 感染者，病毒载量迅速增加，CD4+ T 细胞计数减少。治疗中断期间的病毒反弹与“主要储存库”、静息 CD4+ T 细胞没有明显关联。感染HIV的单核细胞能够避免细胞病理学，并且HAART无法像CD4+ T细胞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存库 残留复制的贡献者。我们假设残余复制是治疗中断后病毒反弹的重要因素，而单核细胞是残余复制的主要贡献者。我们建议分离并比较活性 CD4+ T 细胞、静息 CD4+ 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 期间的残留复制进行系统发育比较，以确定单核细胞和 HIV 感染的贡献。 其他类型的细胞处于残余复制状态。我们将通过在治疗中断前量化 2-LTR DNA 游离环来分离和测量这种持续的复制，并将其与治疗中断期间病毒反弹的血浆病毒 RNA 的程度和速率以及 CD4+ T 细胞的减少相关联。我们还建议在系统发育上比较治疗中断前2-LTR环的C2-V3 env序列与病毒反弹时血浆病毒RNA的C2-V3 env序列，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 HIV 治疗方法和策略。从这项拟议工作中获得的结果将有助于更好地理解原因和问题 对于既往有成功 HAART 临床史的患者，在治疗中断期间经常观察到失败的根源。此外，这项研究可能会产生一种方法来系统地评估个体患者治疗中断的一些风险和益处。