Role of myeloid derived suppressive cells on EcoHIV evasion from vaccine induced T cell immune response

Abstract

Background: Innate immune responses are critical for initiating the CD8 T cells responses for the resolution of infection, and aberrant innate immune response, such as expansion of myeloid derived suppressive cells (MDSC) induced by some viral infection contribute to persistent infection by suppression of T-cell function. Role of innate immune response on prophylactic effects of vaccination has not been carefully studied. Methods: Balb/c mice were immunized with sPD1-p24fc/EP vaccine through intramuscular. After 4 weeks, immunized and non-immunized mice were challenged with EcoHIV via i.p. route. Five mice in each group were euthanized at 1, 2, 3 and 12 weeks post inoculation (wpi). Blood and lymphoid tissues were collected for analysis of virus infection, immune response and T cells function. Results: immunization in mice elicited high frequencies of p24-specific IFN-γ+CD8+ T cells, with on around, 45% of total splenic CD8+ T cells. However, provirus DNA was readily detected in PBMC and spleen in all of the infected mice at every time point tested with no detectable resistant mutations. Compared to non-immunized mice, provirus copies in immunized mice was reduced 2.52 fold at 1, and 2.63 fold at 2 wpi with slight decrease over the following weeks. Infection of mice led to an increase in MDSCs in spleen as early as 7 dpi, which was enhanced at 2 wpi and sustained throughout chronic infection. Expansion of MDSC was associated with decreased p24-specific CD8 T cells number (15% at 2 wpi and decreased overtime by more than 50%), and increased surface expression of PD-1 and Tim 3 and provirus copies. Importantly, MDSCs were primarily infected, and potently suppressed p24-specific memory CD8 T cells proliferation in a dose dependent manner. Depletion of MDSC recovered T cells proliferation in vitro. Conclusions: MDSCs infection and expansion at early stage of infection likely have a critical role in rendering virus resistant to vaccine protection by serving as viral reservoir and suppression of CD8 T cells memory recall and function. This study has important implication for future vaccine strategy design.