These features are also characteristic of elite controllers of HIV whose HIV specific CD8+ T cells are of high avidity, with elevated multifunctional capacity and viral control [48] and [49]. Epacadostat Our previous findings

indicate that the inhibitors avidity of the resultant HIV specific CD8+ T cell repertoire was determined during the priming immunisation [23], this is highly consistent with our current findings where delivering the IL-4C118 adjuvant in the boost only, resulted in a major increase in magnitude of the HIV specific T cell response, without significant avidity enhancement. The results presented here and our recent findings indicate that IL-4/IL-13 not only have significant effects during the induction of the immune response but also affect the functions of activated CD8+ T cells which regulated responsiveness to IL-4/IL-13 by reducing cell surface expression of IL-4Rα [50] and also regulating CD8 co-receptor expression with direct effects on the avidity of CD8+ T cells [51]. The inhibition of IL-13 activity by IL-13Rα2 adjuvanted vaccine [23] was shown to significantly up-regulate CD8 co-receptor expression on KdGag197–205-specific

CD8+ T cells and this correlated with enhanced TCR avidity and poly-functionality [51]. Interestingly, we have BYL719 order also demonstrated that mucosal vaccination induces high avidity HIV-specific T cells with lower IL-4/IL-13 expression and higher CD8-coreceptor densities were detected on KdGag197–205-specific T cells compared to i.m./i.m. delivery [51] On the contrary, co-expression of active IL-4 by a recombinant VV resulted in enhanced IL-4Rα expression, reduced CD8 levels on CD8 T cells, reduced avidity and significantly reduced IFN-γ and TNF-α expression [50] and [51]. Indeed earlier studies

using aminophylline pathogenic Orthopoxviruses expressing IL-4 were shown to severely curtail the development of effective cytotoxic cell mediated immunity with the mice unable to control infection [52] and [53]. As the avidity of a CD8+ T cell can change during the course of an infection [54] and similarly the avidities of different CD8 epitopes are know to be vastly different [43], the true efficacy of the these novel vaccine expressing respective receptors should next be evaluated in a non-human primate model following an SIV challenge. The heterologous FPV-HIV/VV-HIV vaccine strategy was originally designed to elicit a CD8+ T cell mediated immunity towards HIV gag/pol antigen via intracellular processing and MHC-I presentation, however poxviruses can also be good inducers of sustained antibody responses towards viral antigens, one of the features attributed to the long lasting effects of the smallpox vaccine [55]. Previous studies involving co-expression of type-1 cytokines, e.g. IL-2, IL-12, IFN-γ, by viral vaccines to enhance cell-mediated immunity has been associated with reduced serum antibody levels [52], [56] and [57].