Rabies virus-based HIV-1 vaccine vector: impact of antigen presenting cells and immunostimulatory molecules
Human immunodeficiency virus (HIV) has claimed the lives of many across all age groups non-discriminately. Despite great advancements in HIV management through highly active anti-retroviral therapy (HAART), approximately 2.6 million people were infected with HIV in 2009, worldwide. As such, there has been great need to develop preventative and therapeutic vaccines. Previous attempts to develop vaccines against HIV have been unsuccessful, requiring a shift from traditional to more novel designs. The main objective of this study was to improve the immune response to Rabies virus (RABV) vaccine vectors against HIV using dendritic cells (DCs) as adjuvants. To this end, we infected murine bone marrow derived DCs (BMDCs) with a RABV vaccine vector expressing HIV-1 Gag (RIDCs). We observed that cells developed a mature phenotype characterized by high levels of CD86, MHCII, and intermediate levels of CCR7 expression. More importantly, RIDCs mounted strong Gag-specific CD8 + T cell responses in a mouse model even in the presence of pre-existing antibodies against RABV-G in a homologous regimen. Despite this, there were no differences in the magnitude and quality of the CD8 + T cells induced by the RIDCs in comparison to live RABV vectors, probably partly due to equal reliance on endogenous DCs to mediate the immune responses. As such we defined another aim that sought to enhance recruitment of endogenous DCs by means of a RABV vaccine vector expressing HIV-1 Gag and granulocyte-macrophage colony stimulating factor (GM-CSF). We observed that although exogenous GM-CSF led to an increase in DCs, macrophages and B cells in the draining lymph nodes and spleen, there was a paradoxical reduction in HIV-1 Gag specific CD8 + T cells during priming that could be partially due to differences in proliferation. Significantly more interleukin 2 expressing cells were observed in the GM-CSF group, which could have a role in the diminished CD8 T cell response. In conclusion, we show that DCs infected with RABV in vitro are immunogenic in mice. Therefore, in vivo recruitment of endogenous DCs by RABV vaccine vectors has the potential to improve immune responses. Although GM-CSF expressed by a RABV vaccine vector recruits DCs in vivo, it seems to have some off-target effects that diminish the CD8 + T cell immune response. Therefore, GM-CSF should not be used in RABV vaccine development where CD8 + T cell responses are important. These findings could have implications for other vaccine trials using GM-CSF as a vaccine adjuvant.
Wanjalla, Celestine N, "Rabies virus-based HIV-1 vaccine vector: impact of antigen presenting cells and immunostimulatory molecules" (2013). ETD Collection for Thomas Jefferson University. AAI3557327.