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Cited by 18HIV Research and TreatmentVirus-based gene therapy researchHIV/AIDS drug development and treatment

Transcriptional gene silencing limits CXCR4-associated depletion of bone marrow CD34+ cells in HIV-1 infection

Tsukamoto, Tetsuo·2018·AIDS
DOI 10.1097/qad.0000000000001882

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Abstract

OBJECTIVES: Hematological abnormalities that include changes in bone marrow, such as in anemia and pancytopenia, are common among HIV-infected patients, particularly in the advanced stage of disease. Such abnormalities may be caused by a reduced bone marrow function for hematopoiesis. The aim of this study was to determine whether transcriptional gene silencing can help to preserve the hosts' hematopoietic potential in addition to peripheral CD4+ T cells against CCR5-tropic HIV infection. DESIGN: NOD/SCID/JAK3null (NOJ) mice were transplanted with human cord-derived CD34+ cells with or without transduction with a lentiviral vector expressing a promoter-targeting shRNA called PromA. METHODS: At 16 weeks after transplantation, mice engrafted with CD34+ cells were infected with CCR5-tropic HIV-1JRFL. RESULTS: At week 2 postinfection, HIV replication was observed in peripheral blood mononuclear cells and splenocytes. In mice transplanted with unmanipulated CD34+ cells, viral replication was accompanied by a loss of peripheral/spleen CD4+CCR5+ T cells. Interestingly, bone marrow CD34+ cells in HIV-infected mice were also depleted, but in a CXCR4-associated manner. Conversely, the lentiviral transfer of PromA in CD34+ cells prior to transplantation rendered the humanized NOJ mice resistant to HIV replication in CD4+ T cells, resulting in better preservation of peripheral/spleen CD4+CCR5+ T cells and bone marrow CD34+ cells at 2 weeks after infection. CONCLUSIONS: These results indicate that stable gene transfer of PromA to hematopoietic stem cells not only limited HIV replication but also led to preservation of different subsets of hematopoietic cells, including bone marrow stem/progenitor cells and CD4+ T cells.

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  • The efficacy of siPromA in the treatment of HIV-1 has been characterised by in vivo humanised mouse models, demonstrating robust protection against infection by lowering the HIV-1 cell-associated RNA levels in siPromA-expressing CD4+ T cells isolated from blood and lymphoid tissue.

    “Recently, the efficacy of siPromA in the treatment of HIV-1 has been characterised by in vivo humanised mouse models, demonstrating robust protection against infection by lowering the HIV-1 cell-associated RNA levels in siPromA-expressing CD4+ T cells isolated from blood and lymphoid tissue [70,314].”

    From Current State of Therapeutics for HTLV-1 (2024) · cites this paper as [314]

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Authors
Tsukamoto, T.
Affiliations
UNSW Sydney (AU)
Corresponding author
Tsukamoto, Tetsuo
ORCID
Tsukamoto, Tetsuo
Venue
AIDS
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2018-08-24
Volume
32
Issue
13
Pages
1737-1747
ISSN
0269-9370 (ISSN-L)
DOI
10.1097/qad.0000000000001882
OpenAlex
W2803870016
Cited by
18
References
1
Citations by year
2025: 1 · 2024: 5 · 2023: 1 · 2021: 1 · 2020: 5 · 2019: 3 · 2018: 2
FWCI
1.45
Type
journal article
Language
en
Open access
closed
Locations
  • AIDS (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Immunology and Microbiology › Virology › HIV Research and Treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
  • Health Sciences › Medicine › Infectious Diseases › HIV/AIDS drug development and treatment
Keywords
transcriptional silencing, CXCR4, HIV-1 infection, CCR5-tropic HIV, CD34+ hematopoietic stem cells, CD4+ T cell depletion, lentiviral vectors, hematopoiesis, pancytopenia
MeSH terms
Animals, Bone Marrow Cells, Disease Models, Animal, Hematologic Diseases, Leukocytes, Mononuclear, Genetic Therapy, CD4-Positive T-Lymphocytes, HIV-1, HIV Infections, Mice, SCID, Treatment Outcome, Cell Transplantation, Antigens, CD34, Receptors, CCR5, Receptors, CXCR4, Gene Silencing, Mice

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