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Combinatorial anti-HIV gene therapy: using a multipronged approach to reach beyond HAART

Abstract

The ‘Berlin Patient’, who maintains suppressed levels of HIV viremia in the absence of antiretroviral therapy, continues to be a standard bearer in HIV eradication research. However, the unique circumstances surrounding his functional cure are not applicable to most HIV+ patients. To achieve a functional or sterilizing cure in a greater number of infected individuals worldwide, combinatorial treatments, targeting multiple stages of the viral life cycle, will be essential. Several anti-HIV gene therapy approaches have been explored recently, including disruption of the C–C chemokine receptor 5 (CCR5) and CXC chemokine receptor 4 (CXCR4) coreceptor loci in CD4+ T cells and CD34+ hematopoietic stem cells. However, less is known about the efficacy of these strategies in patients and more relevant HIV model systems such as non-human primates (NHPs). Combinatorial approaches, including genetic disruption of integrated provirus, functional enhancement of endogenous restriction factors and/or the use of pharmacological adjuvants, could amplify the anti-HIV effects of CCR5/CXCR4 gene disruption. Importantly, delivering gene disruption molecules to genetic sites of interest will likely require optimization on a cell type-by-cell type basis. In this review, we highlight the most promising gene therapy approaches to combat HIV infection, methods to deliver these therapies to hematopoietic cells and emphasize the need to target viral replication pre- and post-entry to mount a suitably robust defense against spreading infection.

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Acknowledgements

The authors would like to acknowledge the impact of NIH-supported Martin Delaney Collaboratory grant U19 AI 096111 to H.P.K and K.R.J. This effort was supported in part by R01 AI80326 and R01 HL84345 (to H.P.K.), and Bill and Melinda Gates Foundation Grand Challenges Explorations Phase I award 51763 and Phase II award OPP1018811 (to K.R.J.). H.P.K. is a Markey Molecular Medicine Investigator and also supported by the José Carreras/E.Donnall Thomas Endowed Chair for Cancer Research.

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Peterson, C., Younan, P., Jerome, K. et al. Combinatorial anti-HIV gene therapy: using a multipronged approach to reach beyond HAART. Gene Ther 20, 695–702 (2013). https://doi.org/10.1038/gt.2012.98

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  • DOI: https://doi.org/10.1038/gt.2012.98

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