Ongoing HIV replication as a CNS persistence mechanism in the face of cART

面对 cART，持续的 HIV 复制作为 CNS 持续机制

• 批准号: 8881327
• 负责人: Alexander Sigal
• 金额: $ 14.85万
• 依托单位: KWAZULU-NATAL RESEARCH INSTITUTE TB-HIV
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8881327
• 关键词: Address; Adult; Africa; Anti-Retroviral Agents; Astrocytes; Blood; Brain; CD4 Positive T Lymphocytes; Cell Communication; Cell Culture Techniques; Cell Membrane Proteins; Cell membrane; Cells; Child; Clinical; Computer Simulation; Computing Methodologies; Data; Drug effect disorder; Evolution; HIV; HIV-associated neurocognitive disorder; Health; Impaired cognition; Individual; Infection; Lead; Membrane Proteins; Modeling; Patients; Penetrance; Penetration; Pharmaceutical Preparations; Physiology; Plasma; Play; Probability; Public Health; Refractory; Relative (related person); Reporting; Role; Source; South Africa; Testing; Variant; Viral; Viral Load result; Virus; antiretroviral therapy; base; immune activation; insight; macrophage; memory CD4 T lymphocyte; particle; purge; research study; transmission process; virus envelope

DESCRIPTION (provided by applicant): Latency and ongoing replication may both contribute to the HIV reservoir, and the relative importance of each mode of persistence may vary across anatomical compartments. In the CNS, the HIV reservoir may lead to HIV Associated Neurocognitive Disorders (HAND), even in the presence of combination antiretroviral therapy (cART). We previously showed that cell-to-cell HIV spread, a directed form of intercellular HIV transmission where the virus takes advantage of cell interactions to transmit between the interacting cells, results in drug insensitivity across a range of antiretroviral drug concentratios. This insensitivity mechanism is probabilistic: since a locally high concentration of viral particle is transmitted between individual cells, the probability that at least one escapes drug action and proceeds to infect the target cell is high. Insight into the level of viral suppression achieved by cART comes from experiment-based computational models pioneered by Siliciano and co-workers. These models illustrate that the majority of currently used antiretroviral drugs (ARVs) can suppress infection far below the threshold for ongoing replication at concentrations found in the plasma. Hence, the viral particles found in the blood must be from latently infected cells that have been reactivated. Counter to this paradigm, recent data are consistent with ongoing replication in the CNS in the face of cART, including reports of relatively high viral loads, viral evolution in some patients, and immune activation. These markers for ongoing replication occur despite undetectable viral loads in the plasma. Questions remain of 1) whether ongoing replication in the CNS is feasible if current models of drug suppression are corrected for cell- to cell spread and lack of ARV penetration into the CNS, 2) whether cell-to-cell spread of CNS viral variants plays a role in persistent infection of the CNS, and 3) whether ongoing replication in the CNS is of clinical importance. In this study we will test the hypothesis that ongoing replication forms an important component of the viral reservoir in the CNS. This hypothesis will be addressed using the following study aims: 1) To determine feasibility of replication in the CNS in the face of cART. 2) To determine sensitivity of HIV cell-to-cell spread to ARVs in CNS resident cells. 3) To analyze CSF of patients on suppressive cART for viruses of macrophage/macroglial origin as markers for ongoing replication. We anticipate that this study will enable us to determine whether the CNS may support HIV transmission between cells despite suppressive cART. These results will inform control and eradication strategies for the HIV reservoir in the CNS, which are dependent on the persistence mode. Results will be especially relevant to Africa, where HIV burden is highest and where an extensive antiretroviral roll-out is taking place.

描述（由申请人提供）：潜伏期和持续复制都可能有助于HIV储库，并且每种持续模式的相对重要性可能因解剖隔室而异。在CNS中，HIV储库可能导致HIV相关神经认知障碍（HAND），即使在联合抗逆转录病毒治疗（cART）的情况下也是如此。我们先前表明，细胞间HIV传播是细胞间HIV传播的一种定向形式，其中病毒利用细胞相互作用在相互作用的细胞之间传播，导致抗逆转录病毒药物浓度范围内的药物不敏感性。这种不敏感性机制是概率性的：由于局部高浓度的病毒颗粒在单个细胞之间传播，因此至少有一种病毒颗粒逃脱药物作用并继续感染靶细胞的概率很高。深入了解病毒抑制水平， cART来自Siliciano及其同事开创的基于实验的计算模型。这些模型表明，目前使用的大多数抗逆转录病毒药物（ARV）可以抑制感染远低于阈值进行复制在血浆中发现的浓度。因此，在血液中发现的病毒颗粒必须来自潜伏感染的细胞， 被重新激活了与这种范式相反，最近的数据与面对cART在CNS中的持续复制一致，包括相对高的病毒载量、病毒感染和/或病毒感染的报告。 一些患者的进化和免疫激活。尽管血浆中的病毒载量检测不到，但这些持续复制的标志物仍会发生。问题仍然是：1）如果目前的药物抑制模型被校正为细胞-细胞模型， 细胞传播和缺乏ARV渗透到CNS，2）CNS病毒变体的细胞间传播是否在CNS的持续感染中起作用，和3）是否在CNS中持续复制。 CNS具有重要的临床意义。在这项研究中，我们将测试的假设，持续复制形式的一个重要组成部分，病毒水库在中枢神经系统。将使用以下研究目的来解决该假设：1）确定在面对cART时在CNS中复制的可行性。2)确定CNS驻留细胞中HIV细胞间传播对ARV的敏感性。3)分析接受抑制性cART的患者CSF中巨噬细胞/大胶质细胞来源的病毒作为持续复制的标志物。我们预计这项研究将使我们能够确定CNS是否可以支持HIV在细胞间的传播，尽管抑制性cART。这些结果将告知控制和根除策略的HIV水库在中枢神经系统，这是依赖于持久性模式。这些成果将特别关系到非洲，因为非洲的艾滋病毒负担最重，正在广泛推广抗逆转录病毒疗法。