Increased mucosal CD4+ T-cell activation following vaccination with an adenoviral vector in rhesus macaques

Abstract

Background: The possibility that vaccination with Adenoviral vectors increased mucosal T-cell activation remains a central hypothesis to explain the potential enhancement of HIV acquisition within the STEP trial. Modeling this within rhesus macaques is complicated because human Adenoviruses, including Adenovirus type 5 (HAd5), do not productively infect macaques. We created a vector based upon a naturally occurring rhesus macaque Adenovirus (SAdV7) to test whether vaccination with a species-specific Adenoviral vector enhances mucosal Tcell activation within the natural host. Methods: Twelve rhesus macaques were vaccinated 3x intramuscularly with SAdV7 vector. Five HAd5-vaccinated animals were included as controls. PBMC and rectal biopsies were obtained at baseline, multiple times postprime and post-17 week boost (8x/animal), and post-31 week second boost (1x/animal). We assessed rectal mucosal lamina propria and blood for frequency changes of Ad-specific T-cell responses and T-cell activation levels by measuring IFNg, TNFa, IL2, CD25, Ki67, CD69, and HLA-DR. Results: Naturally acquired pre-existing SAdV7-specific CD4+ T-cells were identified in 10/13 macaques within blood and/or rectal mucosa. Following intramuscular SAdV7 vaccination, rectal SAdV7-specific CD4+ T-cell responses increased above baseline in 9/9 animals 2-5 weeks post-prime, and subsequently contracted. Five weeks post-prime, 10/12 animals had rectal SAdV7-specific CD4+ T-cell responses ranging from 0.1-16.84%. As expected, SAdV7-specific CD4+ T-cells expressed CD69 and other activation markers (but not Ki67). Heightened expression of CD25, CD69, and HLA-DR was observed on total rectal memory CD4+ T-cells in SAdV7-vaccinated animals, and maintained 15 weeks after the prime. Interestingly, upregulation of activation markers in rectal mucosa also occurred in HAd5- vaccinated animals. No change in activation was observed in the blood throughout the entire study. Conclusion: These results indicate that peripheral vaccination with an Adenovirus vector can increase the activation of mucosal CD4+ T-cells providing an experimental model to further evaluate the role of hostvector interactions on increased HIV acquisition.