Differential impact of transplantation on peripheral and tissue-associated viral reservoirs

Implications for HIV gene therapy

Christopher W. Peterson, Jianbin Wang, Claire Deleage, Sowmya Reddy, Jasbir Kaur, Patricia Polacino, Andreas Reik, Meei Li Huang, Keith R. Jerome, Shiu Lok Hu, Michael C. Holmes, Jacob Estes, Hans Peter Kiem

Research output: Contribution to journalArticle

4 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere1006956
JournalPLoS Pathogens
Volume14
Issue number4
DOIs
StatePublished - Apr 1 2018
Externally publishedYes

Fingerprint

Genetic Therapy
Transplantation
HIV
Simian Immunodeficiency Virus
Autologous Transplantation
Hematopoietic Stem Cells
Primates
Macaca nemestrina
Satellite Viruses
Lymphoid Tissue
Berlin
Genes
HIV Infections
Gastrointestinal Tract
Vaccination
Lymph Nodes
RNA
Viruses
Safety
DNA

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Immunology
  • Molecular Biology
  • Genetics
  • Virology

Cite this

Differential impact of transplantation on peripheral and tissue-associated viral reservoirs : Implications for HIV gene therapy. / Peterson, Christopher W.; Wang, Jianbin; Deleage, Claire; Reddy, Sowmya; Kaur, Jasbir; Polacino, Patricia; Reik, Andreas; Huang, Meei Li; Jerome, Keith R.; Hu, Shiu Lok; Holmes, Michael C.; Estes, Jacob; Kiem, Hans Peter.

In: PLoS Pathogens, Vol. 14, No. 4, e1006956, 01.04.2018.

Research output: Contribution to journalArticle

Peterson, CW, Wang, J, Deleage, C, Reddy, S, Kaur, J, Polacino, P, Reik, A, Huang, ML, Jerome, KR, Hu, SL, Holmes, MC, Estes, J & Kiem, HP 2018, 'Differential impact of transplantation on peripheral and tissue-associated viral reservoirs: Implications for HIV gene therapy', PLoS Pathogens, vol. 14, no. 4, e1006956. https://doi.org/10.1371/journal.ppat.1006956
Peterson, Christopher W. ; Wang, Jianbin ; Deleage, Claire ; Reddy, Sowmya ; Kaur, Jasbir ; Polacino, Patricia ; Reik, Andreas ; Huang, Meei Li ; Jerome, Keith R. ; Hu, Shiu Lok ; Holmes, Michael C. ; Estes, Jacob ; Kiem, Hans Peter. / Differential impact of transplantation on peripheral and tissue-associated viral reservoirs : Implications for HIV gene therapy. In: PLoS Pathogens. 2018 ; Vol. 14, No. 4.
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