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.
Mother-to-child transmission of HIV-1 accounts for the majority of pediatric HIV infections and is associated with high mortality in resource-limited settings. This proposal will utilize high-throughput sequence and functional analysis to examine the evolution and diversity of the HIV-1 Envelope protein, as well as the biological mechanisms underlying Env-mediated viral transmission. Understanding the genetics and transmission-related biology of early HIV env variants will facilitate the development of improved strategies to prevent primary HIV-1 infection of women and children.