Stable Transcriptional Repression and Parasitism of HIV-1

Surya Shrivastava; Paige Charlins; Amanda Ackley; Heather Embree; Boro Dropulic; Ramesh Akkina; Marc S Weinberg; Kevin V Morris

doi:10.1016/j.omtn.2018.04.011

Stable Transcriptional Repression and Parasitism of HIV-1

Mol Ther Nucleic Acids. 2018 Sep 7:12:12-18. doi: 10.1016/j.omtn.2018.04.011. Epub 2018 May 1.

Authors

Surya Shrivastava¹, Paige Charlins², Amanda Ackley³, Heather Embree⁴, Boro Dropulic⁴, Ramesh Akkina², Marc S Weinberg³, Kevin V Morris⁵

Affiliations

¹ Hematological Malignancy and Stem Cell Transplantation Institute and Center for Gene Therapy, City of Hope-Beckman Research Institute, 1500 Duarte Road, Duarte, CA 91007, USA.
² Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO, USA.
³ Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA, USA.
⁴ Lentigen Technology Inc., Gaithersburg, MD, USA.
⁵ Hematological Malignancy and Stem Cell Transplantation Institute and Center for Gene Therapy, City of Hope-Beckman Research Institute, 1500 Duarte Road, Duarte, CA 91007, USA; Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA, USA. Electronic address: kmorris@coh.org.

Abstract

Gene-based therapies represent a promising treatment for HIV-1 infection, as they offer the potential for sustained viral inhibition and reduced treatment interventions. One approach developed here involves using conditionally replicating vectors (CR-vectors). CR-vectors utilize HIV-expressed proteins to replicate and disseminate along with HIV into the budding viral particles, thereby co-infecting target cellular reservoirs. We generated and characterized several CR-vectors carrying various therapeutic payloads of non-coding RNAs targeted to HIV-1, both transcriptionally and post-transcriptionally. Both virus and vector expression was followed in cell culture systems and T cells 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 manner and that transcriptional targeting of and epigenetic silencing of HIV can be passaged to newly infected cells by the action of the CR-vector, ultimately establishing a sustained parasitism of HIV. Our findings suggest that CR-vectors with modulatory non-coding RNAs may be a viable approach to achieving long-term sustained suppression of HIV-1, leading ultimately to a functional cure.

Keywords: HIV-1; conditionally replicating lentiviral vectors; epigenetic silencing; non-coding RNA; transcription.

Abstract

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