Dynamic HIV-1 Escape from CCR5 Antagonism in vito

HIV-1 体外动态逃避 CCR5 拮抗作用

• 批准号: 7770815
• 负责人: ATHE M. TSIBRIS
• 金额: $ 13.64万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-15 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7770815
• 关键词: AIDS clinical trial group; Alleles; Biological Assay; CCR5 gene; CXCR4 gene; Cell Line; Cell Surface Proteins; Cellular Tropism; Clinical; Clinical Research; Clinical Trials; Communicable Diseases; Complex; Coupled; DNA; Data; Disease; Enrollment; Evolution; Failure; General Hospitals; Genome; HIV; HIV Envelope Protein gp120; HIV-1; Infection; Massachusetts; Mentors; Minor; Minority; Morbidity - disease rate; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Phenotype; Phylogenetic Analysis; Placebos; Plasma; Play; Population; Population Dynamics; Principal Investigator; RNA; Recombinants; Relative (related person); Repetitive Sequence; Resistance; Role; Sampling; Scientist; Speed; System; Technology; Time; Training; Trees; Tropism; V3 Loop; Variant; Viral; Virus; antiretroviral therapy; arm; fitness; improved; in vivo; instructor; mortality; novel; pressure; skills

DESCRIPTION (provided by candidate): The V3 loop of gp120 is both the principal neutralizing determinant of HIV-1 and the main determinant of the virus' cellular tropism. Over the course of host infection, the almost exclusive early use of CCR5 for entry shifts as CXCR4-using viral populations associated with greater morbidity and mortality emerge in approximately 50% of patients over the first 5 years of infection. The advent of antiretrovirals targeting the gp120-CCR5 interaction, coupled with the observation in clinical trials that changes in coreceptor usage represent the major in vivo pathway of HIV escape from these drugs, have re-emphasized the need to improve our understanding of coreceptor usage at the sequence population level. The ability to quantify sequence diversity at V3 and other loci, however, has been limited by the technical and practical constraints of conventional sequencing. We hypothesize that viral coreceptor usage across the HIV quasispecies is more complex than previously appreciated and consists of a multitude of co-circulating CXCR4- and CCR5- using viruses. Viral variants from this wealth of diversity could then be selected under a coreceptor antagonist drug pressure and contribute to the failure of antiretroviral therapy. We further hypothesize that minority CXCR4-using variants are less fit than their CCR5-using counterparts, and will investigate the viral determinants of fitness of minor CXCR4-using viral populations identified by deep sequencing. We propose to 1) Investigate the diversity of coreceptor usage across the HIV quasispecies, identify unique V3 variants, and quantify shifts in their proportions during VCV treatment, 2) characterize the population dynamics of V3 loop sequences during VCV treatment, and 3) investigate the fitness of CXCR4-using minor variants. The candidate is currently an Instructor in the Division of Infectious Diseases at Massachusetts General Hospital and seeks further training in both bench and clinical research skills that will allow him to develop into and independent clinical research scientist. This plan will be conducted under the mentoring of Dr. Daniel Kuritzkes. RELEVANCE: The proposed studies will illuminate the effects of CCR5 antagonist therapy on viral coreceptor usage and V3 loop sequence evolution across the entire quasispecies within an infected host. These studies will contribute to a better understanding of the role these changes may play in disease pathogenesis and inform the most optimal clinical use of HIV-1 CCR5 antagonists.

描述（由候选人提供）：GP120的V3环路既是HIV-1的主要中和决定因素，又是病毒细胞偏向主义的主要决定因素。在宿主感染的过程中，在最初5年的感染中，大约50％的患者出现了CCR5作为CCR5的进入转移的较早使用病毒群体。靶向GP120-CCR5相互作用的抗逆转录病毒的出现，再加上临床试验中的观察结果，即cocector使用的变化代表了HIV从这些药物中逃脱的主要体内途径，重新强调了我们在序列人群水平上对我们对共肽使用的理解的必要性。但是，量化V3和其他基因座序列多样性的能力受到常规测序的技术和实际限制的限制。 我们假设跨HIV准特性的病毒cocector使用比以前所欣赏的更为复杂，并且由使用病毒的众多共同循环的CXCR4和CCR5-组成。然后，可以从共侵袭者拮抗剂的药物压力下选择这种多样性的病毒变异，并导致抗逆转录病毒疗法的失败。我们进一步假设，少数cxcr4使用的变体的拟合度不如使用CCR5使用的对应物，并且将研究通过深度测序鉴定的小CXCR4使用病毒种群适应性的病毒决定因素。我们建议1）研究跨HIV准蛋白酶的共受体使用的多样性，确定独特的V3变体，并量化VCV处理过程中其比例的变化，2）表征V3 Loop序列的V3 Loop序列的人群动态，以及3）研究CXCR4使用的小型变异的适应性。 该候选人目前是马萨诸塞州综合医院的传染病科讲师，并寻求在板凳和临床研究技能上进行进一步培训，这将使他能够发展成独立的临床研究科学家。该计划将在Daniel Kuritzkes博士的指导下进行。 相关性：拟议的研究将阐明CCR5拮抗剂治疗对感染宿主内整个准蛋白酶的病毒cropector使用和V3环序列演变的影响。这些研究将有助于更好地理解这些变化在疾病发病机理中的作用，并为HIV-1 CCR5拮抗剂的最佳临床使用提供信息。