Dynamic HIV-1 Escape from CCR5 Antagonism in vito

描述（由候选人提供）：gp120的V3环既是HIV-1的主要中和决定因素，也是病毒细胞趋向性的主要决定因素。在宿主感染过程中，在感染的前5年，大约50%的患者中出现了几乎完全的早期使用CCR5进行进入转移，因为使用cxcr4的病毒群与更高的发病率和死亡率相关。靶向gp120-CCR5相互作用的抗逆转录病毒药物的出现，加上在临床试验中观察到的辅助受体使用的变化代表了HIV从这些药物中逃逸的主要体内途径，再次强调了在序列群体水平上提高我们对辅助受体使用的理解的必要性。然而，量化V3和其他基因座序列多样性的能力受到传统测序技术和实践的限制。

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.