NOVEL ADENOVIRUS-VECTORED HIV VACCINE THAT KNOCKS THE SOCS1 OFF DENDRITIC CELLS

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Efforts aimed at stimulating immune responses by modifying Human Immunodeficiency virus-1 (HIV) antigens and using a variety of delivery systems and adjuvants have so far failed to produce an HIV vaccine that protects against primary infections, highlighting the need for the continued development of alternative and effective vaccine candidates. Our project is based on findings that the suppressor of cytokine signaling 1 (SOCS1) protein functions as an antigen-presentation attenuator by restricting the Janus-activated kinasesignal transducers and activators of transcription and Toll-like receptor-signaling pathways. To test this hypothesis, the Specific Aims of the project are to: 1) Inhibit DC SOCS1 expression with Ad-mediated delivery of SOCS1 siRNA 2) Determine the effect(s) of SOCS1-silencing on DC function 3) Evaluate the HIV-specific immunes responses induced by SOCS1-silencing Ad-vectored vaccines We have made the following progress during this funding period: + Developed adenovirus vectors that co-express siRNA that target mouse SOCS1 mRNA and transgenes + Demonstrated the SOCS1 siRNA silencing reduced the expression of SOCS1 protein levels in mouse bone marrow-derived mouse dendritic cells + Demonstrated that SOCS1 siRNA-silencing extends the duration of STAT1 phosphorylation as a result of induction by LPS and INF-gamma signaling in bone marrow-derived mouse dendritic cells + Pilot test of the SOCS1-silencing adenovirus vectors demonstrated enhanced antigen-specific CD8+ T cells responses in vivo + Observed higher levels of adenovirus-specific CD8+ T cells in mice vaccinated with SOCS1-silencing vectors + Generated three adenovirus vectors that express SOCS1 siRNAs that target rhesus macaque SOCS1 mRNA The significance of our progress is in the development of a novel adenovirus vector platform designed to directly modulate the immune responses induced by the vaccine. Moreover, the work thus far suggests that by attenuating the down-regulatory role of SOCS1 during the induction of immune responses will serve to significantly improve the vaccine efficacy.