Stable Transcriptional Repression and Parasitism of HIV-1

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 protei...

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Bibliographic Details
Published in:Molecular therapy. Nucleic acids 2018-09, Vol.12, p.12-18
Main Authors: Shrivastava, Surya, Charlins, Paige, Ackley, Amanda, Embree, Heather, Dropulic, Boro, Akkina, Ramesh, Weinberg, Marc S., Morris, Kevin V.
Format: Article
Language:English
Subjects:
Acquired immune deficiency syndrome
AIDS
Cell culture
conditionally replicating lentiviral vectors
Conflicts of interest
epigenetic silencing
Expression vectors
Gene silencing
Gene therapy
HIV
HIV-1
Human immunodeficiency virus
Infections
Lymphocytes
Lymphocytes T
Mutation
Mycophenolic acid
non-coding RNA
Parasitism
Post-transcription
RNA polymerase
transcription
Tumor necrosis factor-TNF
Viral infections
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Summary: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.
ISSN:2162-2531
2162-2531
DOI:10.1016/j.omtn.2018.04.011