Daniel Claiborne, Ph.D.

Progressive T cell exhaustion and dysfunction due to continuous antigen exposure is a hallmark of chronic viral infections. In situations of uncontrolled HIV replication, we have observed a striking and progressive increase in the co-expression of multiple inhibitory receptors on CAR T cells in humanized mice. Additionally, CAR T cells isolated from viremic humanized mice display attenuated effector function ex vivo when compared to the transferred T cell product at baseline. Using this model system, and through a combination of transcriptomics and ex vivo functional assays, the Claiborne lab intends to map the initiation and maintenance of dysfunctional T cell subsets in an effort to uncover gene pathways/programs that can be targeted to prevent or reverse T cell exhaustion – with the goal of engineering more potent CAR T cell immunotherapies.

We have recently developed a novel in vitro model system for chronic antigen stimulation of CAR T cells with the ability to specifically titrate antigen dosing as well as remove antigen stimulation at any time. Using this unique model system, we have mapped the longitudinal and concomitant expression of multiple inhibitory receptors on human CD4 and CD8 CAR T cells. We further aim to understand the functional consequences of multiple inhibitory receptor expression, whether periods of rest due to antigen removal can reverse certain inhibitory receptor profiles, and which profiles are indicative of long-term transcriptional reprogramming.

Previous work by the lab has demonstrated that the intrinsic viral replicative capacity (vRC) of the transmitted/founder virus can greatly impact the disease course of HIV-infected individuals. Individuals infected with high-vRC variants display exacerbated immunopathology characterized by T cell activation and exhaustion, concomitant with rapid CD4+ T cell loss. This may also represent an unrecognized hurdle for a functional HIV cure, as individuals with high-vRC viruses may be more refractory to CAR T cell therapy or other interventions. The lab endeavors to use a previously generated suite of chimeric viruses exhibiting distinct vRC phenotypes to define the extent to which vRC affects CAR T efficacy in vitro and in vivo and to elucidate the mechanisms responsible.

Recent evidence in a humanized mouse model of acute lymphoblastic leukemia demonstrates that interactions between CAR T cells and the innate immune system can enhance CAR T cell function but can also contribute to cytokine release syndrome (Norelli M et al., Nature Medicine, 2018). During HIV infection, vigorous innate immune responses ultimately contribute to chronic immune activation and inflammation, which is associated with accelerated pathogenesis. These data suggest a complex role for components of the innate immune system, with the potential for enhancing or attenuating functions, in modulating CAR T cell efficacy in the context of HIV infection. We have created a series of reagents to specifically ablate or enhance monocyte function in humanized mice and endeavor to use this in vivo system to elucidate the role of the innate immune system in affecting HIV-specific CAR T cell function.