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PLoS Pathog. 2018 Apr 19;14(4):e1006956. doi: 10.1371/journal.ppat.1006956. eCollection 2018 Apr.

Differential impact of transplantation on peripheral and tissue-associated viral reservoirs: Implications for HIV gene therapy.

Author information

1
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States of America.
2
Department of Medicine, University of Washington, Seattle, WA, United States of America.
3
Sangamo Therapeutics, Richmond, CA, United States of America.
4
AIDS and Cancer Virus Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD, United States of America.
5
Washington National Primate Research Center, Seattle, WA, United States of America.
6
Vaccine and Infectious Diseases Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States of America.
7
Department of Laboratory Medicine, University of Washington, Seattle, WA, United States of America.
8
Department of Pharmaceutics, University of Washington, Seattle, WA, United States of America.
9
Department of Pathology, University of Washington, Seattle, WA, United States of America.

Abstract

Autologous transplantation and engraftment of HIV-resistant cells in sufficient numbers should recapitulate the functional cure of the Berlin Patient, with applicability to a greater number of infected individuals and with a superior safety profile. A robust preclinical model of suppressed HIV infection is critical in order to test such gene therapy-based cure strategies, both alone and in combination with other cure strategies. Here, we present a nonhuman primate (NHP) model of latent infection using simian/human immunodeficiency virus (SHIV) and combination antiretroviral therapy (cART) in pigtail macaques. We demonstrate that transplantation of CCR5 gene-edited hematopoietic stem/progenitor cells (HSPCs) persist in infected and suppressed animals, and that protected cells expand through virus-dependent positive selection. CCR5 gene-edited cells are readily detectable in tissues, namely those closely associated with viral reservoirs such as lymph nodes and gastrointestinal tract. Following autologous transplantation, tissue-associated SHIV DNA and RNA levels in suppressed animals are significantly reduced (p ≤ 0.05), relative to suppressed, untransplanted control animals. In contrast, the size of the peripheral reservoir, measured by QVOA, is variably impacted by transplantation. Our studies demonstrate that CCR5 gene editing is equally feasible in infected and uninfected animals, that edited cells persist, traffic to, and engraft in tissue reservoirs, and that this approach significantly reduces secondary lymphoid tissue viral reservoir size. Our robust NHP model of HIV gene therapy and viral persistence can be immediately applied to the investigation of combinatorial approaches that incorporate anti-HIV gene therapy, immune modulators, therapeutic vaccination, and latency reversing agents.

PMID:
29672640
PMCID:
PMC5908070
DOI:
10.1371/journal.ppat.1006956
[Indexed for MEDLINE]
Free PMC Article

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