Mechanisms of Ad5-Induced Immune Dysfunction

Abstract

The failure of an Adenovirus 5 (Ad5)-based human immunodeficiency virus type 1 (HIV-1) vaccine in the STEP trial warranted a detailed evaluation of the immunological properties of Ad5. Previous studies have revealed that immunization with Ad5 induces a partially exhausted T cell response but the mechanism of Ad5-induced immune dysfunction is unknown. Using classical animal models, it has been shown that altering antigen dose, and modulating the PD-1/PD-L1 signaling pathway, or modulating regulatory T cells (Tregs) can influence the quality of memory CD8 T cell. Therefore, we interrogated whether these factors play similar roles in Ad5-induced dysfunction. Here, we show that reducing Ad5 vaccine dose induces highly functional memory CD8 T cell responses, characterized by lower PD-1 expression, higher cytokine co-expression, and an improved recall expansion following a heterologous boost. Interestingly, we show that the dysfunctional recall of Ad5-primed T cells following high-dose immunisation may partly be mediated by a PD-1-dependent CD8 T cell intrinsic phenomenon, as blockade of PD-L1 leads to a substantial improvement in anamnestic T cell expansion. Furthermore, we provide preliminary data suggesting that Treg may not play a crucial role in the development of Ad5-induced dysfunction. Overall, our data contribute to the understanding of the mechanism of Ad5-induced immune dysfunction, and may be relevant for improving vaccination modalities for HIV and other chronic viral infection.