Targeting Tfh differentiation to increase the magnitude and durability of antibody responses in infant rhesus macaques after SHIV infection

About This Grant

PROJECT SUMMARY Approximately 120,000 young children are newly infected with HIV-1 each year. In the absence of antiretroviral therapy (ART), infants have a mortality rate of up to 50% within the first 2 years of life, but administration of ART reduces morbidity and mortality and is now implemented early in life for most children. Unfortunately, even with ART, children under 5 years old are at higher risk of mortality than older children or adults on ART. While a number of factors may contribute to this increased mortality, a hyporesponsive immune system likely plays an important role. Children living with HIV-1 have been shown to have diminished antibody responses, with a lack of HIV-1 seroconversion after early ART and poorer antibody responses than their uninfected peers to common childhood vaccinations. The overarching goal of our research is to improve HIV- and vaccine-specific antibody development in children living with HIV-1 by targeting the differentiation of T follicular helper (Tfh) cells, which provide critical survival and differentiation signals to B cells. Tfh differentiation is limited in infants compared to adults, and our preliminary analysis of pediatric clinical samples identified elevated Helios expression in infant CD4+ T cells as a potential regulator of Tfh cell development. CRISPR knock out of Helios in naïve CD4+ T cells from cord blood or healthy adult blood before in vitro Tfh differentiation revealed a negative correlation between the frequency of Helios+ cells remaining and subsequent Tfh cell differentiation. We hypothesize that administration of a Helios degrader, DKY709, to target Helios expression in CD4+ T cells will improve Tfh cell differentiation and subsequent antibody development after vaccination or infection. Due to the uniquely high expression of Helios in infant CD4+ T cells but not adults, we will use the infant rhesus macaques model of HIV to determine if Helios degradation by DKY709 will improve the magnitude and durability of antibody responses to 1) vaccines administered to SHIVSF162P3 infected or naïve animals and 2) SHIVSF162P3 after early ART administration. Together these studies will provide important preliminary data about the capacity of Helios degradation to improve Tfh differentiation and humoral immune responses in infants, particularly in the context of SHIV infection. Importantly, the results from either aim will provide critical information that can be used as the basis for future research proposals. The candidate is currently a Research Assistant Professor in the Vaccine and Gene Therapy Institute, which is located on the Oregon Health & Science University West Campus with the Oregon National Primate Research Center. This provides a highly collaborative environment in which to do HIV research with nonhuman primate models. Building on her previous research studying immune responses in clinical cohorts, this proposal will further her training in using the infant SHIV infection model to assess immune responses to therapeutic interventions and in developing clinical trials to translate research findings into infants. Completion of the career development plan and innovative research study will provide a strong foundation upon which to build a successful independent research career in pediatric HIV-1 immunology.