Role of Specific Drugs and Mutations in Partial Suppression of Viremia

特定药物和突变在部分抑制病毒血症中的作用

• 批准号: 8157481
• 负责人: Frank Maldarelli
• 金额: $ 24.94万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 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/8157481
• 关键词: Mutation; Pharmaceutical Preparations; Role; Viremia

To analyze the correlation between phenotype/genotype to selected antiretroviral agents and short-term change in viral load upon discontinuation of a single antiretroviral agent from a failing regimen, one drug in a failing multidrug regimen is withdrawn for a limited period of time, and then restored. By monitoring changes in both viremia and genotype (by the limiting dilution assay), we can discern whether the drug was contributing to partial suppression of virus, and also determine which mutations are associated with resistance to that drug, and their effect on both replication of the virus and resistance to the drug. In collaboration with Dr. Vinay Pathak, we have begun to analyze the entire RT sequence to determine whether additional changes in the RNAse H portion of RT are associated with partial drug suppression. With Dr. Anuradha Ganesan we have initiated a new site for this protocol at the National Naval Medical Center. The need for new antiviral agents continues, and identification of cellular pathways participating in HIV-1 maturation by E. Freed in the DRP and others have suggested novel strategies to inhibit virus replication by disrupting host-viral interactions required for virion maturation. Specifically, we are studying the cholesterol lowering agent, atorvastatin, which reduces viral yield and infectivity in vitro by reducing cholesterol in lipid rafts required for HIV-1 maturation. Previous observations by HVIB and others have yielded conflicting evidence on the potential antiviral benefit of statin therapy. In collaboration with National Naval Medical Centers in Bethesda and San Diego (Drs. Ganesan and Crum-Clanfione) and with NIH Clinical Center (Masur), the HVIB conducted the first randomized, placebo-controlled trial of atorvastatin in HIV-1 infection (Protocol 06-I-0197). This study included a detailed analysis of host and viral genetics as well as extensive immunophenotyping; as a result we investigated the overall utility of the statin approach in inhibiting HIV-1 replication, and studied the genetic correlates associated with success or failure the utility of this approach and identify immune effects of statin therapy. We found that 80 mg Atorvastatin therapy for 8 weeks duration did not specifically decrease HIV-1 RNA levels, but did affect immunophenotyping profiles with significant decreases in proportion of CD8CD38 cells in peripheral blood (Ganesan et al., submitted). These studies illustrate the complex interplay between immune and viral effects during HIV infection, and demonstrate the ability of statin therapy to decrease cellular immune activation parameters independently of any effect on viremia per se. We are currently analyzing additional markers of inflammation (e.g., IL-6, D-dimer) for effects of statin therapy on soluble markers of inflammation. Several clinical groups at NIH (I. Sereti, NIAID; J. Mican, NIAID) have engaged DRP investigators to collaborate in analyzing resistance profiles arising in patients on standard and experimental therapy (Porter, B.O., et al., 2009). In addition, the HVIB serves as a primary resource for interpretation of genotypic and phenotypic information for a number of protocols, notably protocol 95-I-0072 (J. Mican, NIAID PI, F. Maldarelli, Associate Investigator), used in training of infectious disease fellows, and for local referral of difficult cases. These interactions support mentoring of trainees and also result in new and clinically relevant information regarding HIV and antiviral therapy. In collaboration with NIAID (J. Mican, A. Pau), HVIB investigators recently characterized a previously unrecognized interaction between the antiretroviral ritonavir and local epidural hydrocortisone preparations. Understanding the host metabolic contribution to antiretroviral drug metabolism is an integral aspect of understanding such interactions, and HVIB participates in active research in this area (Robertson, et al., 2009). In addition, with J.Mican and H.C. Lane (NIAID), we are in the process of characterizing a new drug insertion mutation in Subtype C reverse transcriptase with novel phenotypic resistance properties. We have also participated in post-hoc analyses of resistance profiles of individuals enrolled in NIAID-South Africa collaborative protocols of antiretroviral therapy (Phidisa II). We have compared emergence of mutations in a cohort of over 1700 patients enrolled in a randomized study comparing NNRTI and PI containing regimens. A direct clinical outcome of the expertise gained in these studies has been in evaluating cases of occupational exposure to HIV that have occurred in NIH clinical and veterinary settings. Exposure to drug resistant virus as well as novel HIV and recombinant SHIV experimental viruses requires detailed considerations for post exposure prophylaxis (PEP). HVIB has been consulted by Occupational Medical Services for exposures occurring at NIH and has been instrumental in assisting in the construction of non-standard PEP regimens designed for specific exposures. [Corresponds to Project 4 in the April 2007 site visit report of the Host-Virus Interaction Branch, HIV Drug Resistance Program]

为了分析表型/基因型与选定的抗逆转录病毒药物的相关性与在失败方案中停用单个抗逆转录病毒剂后，病毒载量的短期变化与失败的多种药物中的一种药物在有限的时间内被撤销，然后恢复。通过监测病毒血症和基因型的变化（通过限制稀释测定），我们可以辨别该药物是否有助于部分抑制病毒，并确定哪些突变与对该药物的耐药性及其对病毒的复制和对药物的抗性的影响有关。与Vinay Pathak博士合作，我们开始分析整个RT序列，以确定RT的RNase H部分的其他变化是否与部分药物抑制有关。在国家海军医疗中心，我们在Anuradha Ganesan博士的情况下为该方案启动了一个新站点。 对新抗病毒药物的需求仍在继续，并鉴定出E.释放在DRP中参与HIV-1成熟的细胞途径，而其他人则提出了新的策略来抑制病毒复制，通过破坏毒病毒成熟所需的宿主 - 病毒相互作用。具体而言，我们正在研究胆固醇降低剂Atorvastatin，从而通过减少HIV-1成熟所需的脂质筏中的胆固醇来降低体外病毒产量和感染性。 HVIB和其他人的先前观察结果证明了他汀类药物疗法潜在的抗病毒药品。与贝塞斯达和圣地亚哥国家海军医疗中心（Ganesan和Crum-Clanfione博士）以及NIH临床中心（MASUR）合作，HVIB进行了首次随机，安慰剂对照试验，对HIV-1感染中的Atorvastatin进行了Atorvastatin的试验（协议06-I-I-0197）。这项研究包括对宿主和病毒遗传学以及广泛的免疫表型的详细分析。结果，我们研究了他汀类药物方法在抑制HIV-1复制方面的总体效用，并研究了与成功或失败相关的遗传相关性，该方法的效用并确定了他汀类药物治疗的免疫作用。我们发现，持续8周的80 mg atorvastatin疗法并未明确降低HIV-1 RNA水平，但确实影响了外周血中CD8CD38细胞比例显着降低的免疫表型谱（Ganesan等人，已提交）。这些研究说明了HIV感染期间免疫和病毒作用之间的复杂相互作用，并证明了他汀类药物治疗能够降低细胞免疫激活参数的能力，而不是对病毒血症本身的任何影响。我们目前正在分析他汀类药物治疗对炎症可溶性标记的影响的其他炎症标记（例如IL-6，D-二聚体）。 NIH的几个临床组（I. Sereti，Niaid; J. Mican，Niaid）聘请DRP研究者合作，以分析标准和实验疗法患者产生的耐药性（Porter，B.O.等，2009）。此外，HVIB是解释许多方案的基因型和表型信息的主要资源，尤其是方案95-I-i-0072（J. Mican，Niaid Pi，F。Maldarelli，副研究人员），用于培训感染性疾病研究员的培训以及困难局部的局部引用。这些相互作用支持对学员的指导，还导致有关艾滋病毒和抗病毒疗法的新的和临床上有关的信息。 HVIB研究人员与NIAID（J. Mican，A。Pau）合作，最近表征了抗逆转录病毒利托那韦与局部硬膜外氢化可的松制剂之间以前未被认可的相互作用。了解宿主代谢对抗逆转录病毒药物代谢是理解这种相互作用的组成部分，而HVIB参与了该领域的积极研究（Robertson等，2009）。 此外，J.Mican和H.C.泳道（NIAID），我们正在表征具有新的表型抗性特性的亚型逆转录酶中新药插入突变的过程。 我们还参与了抗逆转录病毒疗法的NIAID-南非洲协作方案（Phidisa II）的耐药性概况的事后分析（Phidisa II）。我们已经比较了1700多名与含有NNRTI和PI含有方案的随机研究的患者组中突变的出现。这些研究中获得的专业知识的直接临床结果是评估NIH临床和兽医环境中发生的职业暴露于HIV的病例。暴露于耐药病毒以及新型的HIV和重组SHIV实验病毒需要详细考虑暴露后预防（PEP）。职业医疗服务已咨询了HVIB，以进行NIH发生的暴露，并在协助建造专为特定暴露的非标准PEP方案中发挥了作用。 [对应于2007年4月的宿主病毒互动分支的现场访问报告，艾滋病毒耐药性计划的项目4]