Aberrant innate immune activation facilitates EcoHIV evasion from vaccine-induced protection

Abstract

Abstract Aberrant innate immune response during acute phase of infection causes persistent viral infection through suppression of T-cell function. Understanding the impact of this aberrant innate immune activation on vaccine-conferred protection is critical regarding development of effective vaccine against chronic disease. Here, using EcoHIV mice model and a novel DC-targeting DNA vaccine that elicited high frequencies of GAG-specific, broadly reactive, and polyfunctional cytotoxic CD8+ T cells, we show that aberrant innate immune activation at early stage of infection rendered EcoHIV resistant to vaccine protection by suppressing T cells proliferation and function. We found that despite high frequencies of p24-specific IFN-γ+CD8+ T cells elicited by vaccination, EcoHIV have fallen short of effective recall of antiviral T cell immunity induced by prophylactic vaccination in vivo. Provirus DNA was readily detected in PBMC and spleen in all of the infected mice without detectable resistant mutations. Compared to non-immunized mice, provirus copies in immunized mice were decreased only at 1 and 2 weeks post viral inoculation without further decrease over the following weeks. Further investigation revealed that EcoHIV infected multiple DC subsets, and CD11b+ myeloid derived cells within 7 dpi, and induced quick expansion of eosinophils and monocytic cells in spleen, which peaked at 14 dpi and remained high at 21 dpi. The expansion of monocytic cells was associated with down-regulation of CD80 and CD86, up-regulation of PD-L1/L2 on multiple dendritic cell subsets, PD-1+ and Tim+ CD8 T cells, compromised capacity of DCs in stimulating CD4 and CD8 T cells proliferation, and suppressed viral-specific CD8 T cells proliferation in vitro.