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

Emory University, Atlanta GA

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Abstract

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 kinase[unreadable]signal transducers and activators of transcription and Toll-like receptor-signaling pathways. The purpose of our project was 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 During the reporting period we: + Developed a panel of adenovirus-based vectors that co-express (i) SOCS1 siRNA and (ii) the reporter gene Green Fluorescent Protein (GFP) or antigen gene HIV-1 gag. + We have tested the effects of SOCS1 siRNA on dendritic cell phenotype. No negative effects on dendritic cell maturation were observed. + Developed a Western blot approach for detecting the effects of SOCS1 siRNA expression on the phosphorylation of STAT1 following INF-gamma stimulation as a surrogate measurement of SOCS1 siRNA-silencing. The results from these experiments suggest that our SOCS1 siRNA-expressing vectors enhance the STAT1 signaling pathway and support our hypothesis. The significance of the progress made during this period primarily relates to the development of a novel adenovirus vector platform that is 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.