Mechanisms of Ad5-Induced Immune Dysfunction
Metadata
Show full item recordCitation
Alayo, Quazim A. 2016. Mechanisms of Ad5-Induced Immune Dysfunction. Master's thesis, Harvard Medical School.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.Terms of Use
This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAACitable link to this page
http://nrs.harvard.edu/urn-3:HUL.InstRepos:33789913
Collections
Contact administrator regarding this item (to report mistakes or request changes)