Molecular and functional correlates of HIV-1 transmission in MTCT

我的职业目标是在顶尖的研究机构作为一名独立的研究者，通过将免疫学和细胞生物学结合起来，进一步了解人类健康和疾病。对疾病过程的分子理解对于开发新的治疗和预防方法至关重要。本研究旨在探讨HIV-1母婴传播（MTCT）过程中病毒进入的分子和生物学机制。完成这一提案的目的，不仅可以提高我们对HIV传播和慢性感染过程中env进化的理解，而且可以帮助我实现我的职业目标。研究艾滋病毒传播的潜在机制将增强我对假设驱动的、以患者为导向的研究的理解，而在麻省大学医学院的分子医学项目工作将使我能够与马萨诸塞州的杰出科学家建立牢固而持久的关系。

DESCRIPTION (provided by applicant): Training Program My career goal is to further the understanding of human health and disease by integrating immunology with cell biology as an independent investigator at a top research institution. A molecular understanding of disease processes is critical for developing new treatment and prevention methods. This proposal aims to investigate the molecular and biological mechanisms underlying viral entry during mother-to-child transmission (MTCT) of HIV-1. Accomplishing the aims of this proposal will not only improve our understanding of the evolution of env during HIV transmission and chronic infection, but will also help me achieve my career goals. Studying the mechanisms underlying HIV transmission will enhance my understanding of hypothesis-driven, patient-oriented research, and working in the Program in Molecular Medicine at UMass Medical School will allow me to build strong and lasting relationships with prominent scientists throughout Massachusetts. Research Plan During mucosal transmission of HIV, the diversity of transmitted strains is markedly restricted compared to the quasispecies in the source patient or that evolves over time in infected individuals. It remains unclear whether this bottleneck effect is stochastic (random) o due to active selection mediated by host factors and/or viral characteristics. I will evaluate the relative contributions of active vs. stochastic selection during HIV viral entry using a model of MTCT, where transmission pairs and timing of infant infection are readily identified. I will use serial samples from two well-characterized, unique cohorts of HIV-1 infected women who transmitted HIV-1 at birth or through breastfeeding. These cohorts include women with chronic HIV-1 infection (CI) and women who acquired primary HIV-1 infection post-partum (acutely infected, AI). I will combine phylogenetic sequence analyses (combining single genome amplification with high-throughput deep sequencing) and functional assays (CD4 and co-receptor use, cell tropism, and viral entry phenotype) to assess the relationship of founder viruses to maternal viral variants. By comparing maternal viral variants to founder viruses in the CI and AI cohorts, I will quantify the relative contributions of stochastic and active selection, determine when selective pressures may act on the HIV-1 Envelope (Env) protein, and determine whether founder HIV env variants are better adapted for MTCT than non-transmitted variants. Identifying the biologic properties common to transmitted Env variants and mapping the genetic bases of these properties will improve our understanding of HIV-1 entry, and have the potential to identify critical components of Env-mediated entry for viral entry. These results of these studies will reveal whether targeting specific Env functional properties (tropism, infectivity) hold promise for blocking primary HIV infection of women and children, helping to guide the development of novel strategies to prevent primary HIV-1 infection of women and infants.