532. Stable Transcriptional Repression, Gene Excision, and Parastism of HIV by Conditionally Replicating Lentiviral Vectors

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Gene-based therapies represent a promising therapeutic paradigm for the treatment of HIV, as they have the potential for sustained viral inhibition via reduced treatment interventions. One innovative approach developed here involves using conditionally replicating vectors (CR-Vectors), as these vectors utilize HIV-expressed proteins to replicate. These vector payloads can spread along with HIV into the budding viral particles, and co-infect target cells, essentially disseminating to HIV infected cells. We have generated and characterized CR-Vectors carrying therapeutic payloads consisting of various non-coding RNA regulatory expression cassettes, which modulate HIV both transcriptionally and post-transcriptionally, as well as CRISPR directed excision machinery. Notably, we have followed both virus and vector expression in T-cells and in vivo in the presence and absence of mycophenolic acid (MPA) selection. We find here that CR-Vectors functionally suppress HIV expression in a long-term stable and potent manner in both the presence and absence of MPA; and that transcriptional targeting is more potent at modulating stable suppression of HIV than post-transcriptional targeting or CRISPR directed excision of HIV. This suppression may be physiologically relevant, as it appears to drive HIV to a sustained non-pathogenic set point. Our findings suggest that CR-Vectors with modulatory non-coding RNAs may be a viable approach to achieving long-term stable suppression of HIV leading ultimately to a functional cure.