HIV Residual Replication and Drug Holidays

HIV 残留复制和药物假期

• 批准号: 7312159
• 负责人: Eric Lorenzo
• 金额: $ 16.15万
• 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/7312159
• 关键词: AIDS therapy; HIV envelope protein; Puerto Rico; T lymphocyte; antiviral agents; disease /therapy duration; disease reservoirs; drug administration rate /duration; human immunodeficiency virus; human subject; microorganism disease chemotherapy; molecular cloning; monocyte; nucleic acid sequence; patient oriented research; polymerase chain reaction; provirus; virus DNA; virus RNA; virus load; virus replication

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.

高活性抗逆转录病毒疗法（HAART）的联合治疗显著降低了艾滋病毒感染者的发病率和死亡率。尽管长期治疗，传染性艾滋病毒仍在继续复制并潜伏在储存库中，这对根除艾滋病毒造成了重大障碍。由于严重的副作用和/或高昂的费用而中断治疗的大多数艾滋病毒感染者，迅速发展为病毒载量增加和CD4+ t细胞计数减少。这种病毒在治疗中断期间的反弹与“主要储存库”，即静止的CD4+ t细胞没有明确的关联。受HIV感染的单核细胞能够避免细胞病理，而HAART无法像在CD4+ T细胞中那样有效地阻断病毒在这些细胞中的复制，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和