In vivo modeling of IgH-reprogrammed B cells in non-human primates

Scripps Research Institute, The, La Jolla CA

Investigators

Abstract

PROJECT SUMMARY Decades of research on HIV have turned this infection into a manageable chronic condition instead of a terminal illness. However, a vaccine that can prevent or eliminate infection remains elusive, viruses resistant to antiretroviral therapy (ART) are on the rise, and individuals who have to discontinue ART have few alternatives that can suppress viral replication. Thus, new, innovative approaches to functionally cure HIV infection are needed. Our Program Project team members have pioneered genetically engineering B cells to express anti- HIV broadly neutralizing antibodies (bNAbs) to address this need, and these approaches elicit robust, durable anti-HIV bNAb titers in mice. While promising, this research requires translation into large animal models like rhesus macaques to develop this approach into a therapy for people living with HIV. The objective of Project 3 is to translate our team's prior studies in mice to macaques and elicit durable anti-HIV bNAb titers from IgH- reprogrammed macaque B cells. This translation is necessary to obtain the long-term goal of developing an engineered B cell therapy for HIV. In preliminary studies, Dr. Voss has shown that macaque B cells can be edited ex vivo, infused back into autologous donors, and engaged to produce VRC01 IgG, an anti-HIV bNAb. However, the titers were short-lived, and additional vaccinations did not increase VRC01 titers, indicating a failure to form durable memory. Here, we will continue this research and pursue a complementary approach to elicit durable, engineered antibody memory in rhesus macaques. Specific Aim 1 will build upon our preliminary studies using ex vivo B cell targeting approaches and will define the behavior of ex vivo engineered B cells in vivo by studying where they home, what B cell subset they differentiate into, and their molecular make-up after infusion. This new information, combined with reagents and research performed with the scientific cores and other projects, will enable us to improve upon our previous work in macaques and elicit durable VRC01 antibody titers and memory. Specific Aim 2 will pursue a complementary approach to obtain durable VRC01 antibody titers in macaques using in vivo B cell targeting approaches recently established by members of our team. Similar to Specific Aim 1, we will study the biology of in vivo engineered B cells. In the short-term, this research will translate these two approaches for eliciting durably engineered antibody memory into macaque models, which will set the stage for testing the efficacy of this therapy in rhesus macaque models of HIV infection. In the long-term, we expect this to lead to a new therapy that can cure HIV.