HIV-1 infection of hematopoietic progenitor cells in vivo in humanized mice

Nixon, Charles R.; Vatakis, Dimitrios N.; Reichelderfer, Scott N.; Dixit, Dhaval; Kim, Sohn G.; Uíttenbogaart, Christel H.; Zack, Jerome A.

doi:10.1182/blood-2013-04-496950

Cited by 45 publications

(40 citation statements)

References 37 publications

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“…Humanized mouse models have been used widely to investigate the mechanisms of HIV-1 immunopathogenesis, including functionally defining the role of regulatory T cells (41), pDCs (30), and other cells (29) in acute and chronic HIV-1 infection. In the present study, we found that human ILC3 subsets were functionally developed in all lymphoid organs in NRG-hu mice and preferentially resided in the spleen and mLN.…”

Section: Discussionmentioning

confidence: 99%

“…We thus took advantage of the well-developed humanized mouse model to investigate the function and role of ILC3 in HIV-1 pathogenesis (28)(29)(30)(31) Figure 2). We found that ILC3s were efficiently developed in all lymphoid organs of humanized mice including spleen, mesenteric lymph node (mLN), peripheral lymph node (pLN), BM, and peripheral blood lymphocytes (PBL) ( Figure 2A).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Plasmacytoid dendritic cells promote HIV-1–induced group 3 innate lymphoid cell depletion

Zhang¹,

Liu²,

Zhao³

et al. 2015

Journal of Clinical Investigation

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Plasmacytoid dendritic cells promote HIV-1–induced group 3 innate lymphoid cell depletion

Zhang¹,

Liu²,

Zhao³

et al. 2015

Journal of Clinical Investigation

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“…Because some analyses of plasma virus found that certain identical sequences predominate in circulation over multiple time points, it was proposed that latently-infected stem cells, with the capacity for self-renewal, contributed clonal virus upon intermittent activation [3]. Indeed, a number of studies have provided evidence that HIV can infect CD34 + bone marrow progenitors [7–9,34–36]. A study of HIV-infected people in Africa revealed that HIV-1 subtype C could infect HSPCs in vitro and in vivo .…”

Section: Defining Latent Reservoirsmentioning

confidence: 99%

Targeting HIV latency: resting memory T cells, hematopoietic progenitor cells and future directions

Sebastian

Collins²

2014

Expert Review of Anti-infective Therapy

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Current therapy for HIV effectively suppresses viral replication and prolongs life, but the infection persists due, at least in part, to latent infection of long-lived cells. One favored strategy towards a cure targets latent virus in resting memory CD4+ T cells by stimulating viral production. However, the existence of an additional reservoir in bone marrow hematopoietic progenitor cells has been detected in some treated HIV-infected people. This review describes approaches investigators have used to reactivate latent proviral genomes in resting CD4+ T cells and hematopoietic progenitor cells. In addition, we review approaches for clearance of these reservoirs along with other important topics related to HIV eradication.

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“…In addition, lentiviral-mediated gene delivery of the HSV-tk/GCV suicide system has been used in HIV-infected cells 32 and to control graft-versus-host disease in a phase I/II clinical trial in patients with leukemia 74 . Recently, it has been shown that HIV can infect cells of the hematopoietic lineage in vivo, 75 and novel lentiviral vectors targeting CD34 + hematopoietic progenitor cells have been described 76 . Bone marrow gene therapy is an attractive technology for HIV antiviral therapies (reviewed by Herrera-Carrillo et al 17 …”

Section: Discussionmentioning

confidence: 99%

Expression of Herpes Simplex Virus Thymidine Kinase/Ganciclovir by RNA Trans-Splicing Induces Selective Killing of HIV-Producing Cells

Ingemarsdotter

Poddar

Mercier

et al. 2017

Molecular Therapy - Nucleic Acids

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Antiviral strategies targeting hijacked cellular processes are less easily evaded by the virus than viral targets. If selective for viral functions, they can have a high therapeutic index. We used RNA trans-splicing to deliver the herpes simplex virus thymidine kinase-ganciclovir (HSV-tk/GCV) cell suicide system into HIV-producing cells. Using an extensive in silico bioinformatics and RNA structural analysis approach, ten HIV RNA trans-splicing constructs were designed targeting eight different HIV splice donor or acceptor sites and were tested in cells expressing HIV. Trans-spliced mRNAs were identified in HIV-expressing cells using qRT-PCR with successful detection of fusion RNA transcripts between HIV RNA and the HSV-tk RNA transcripts from six of ten candidate RNA trans-splicing constructs. Conventional PCR and Sanger sequencing confirmed RNA trans-splicing junctions. Measuring cell viability in the presence or absence of GCV expression of HSV-tk by RNA trans-splicing led to selective killing of HIV-producing cells using either 3′ exon replacement or 5′ exon replacement in the presence of GCV. Five constructs targeting four HIV splice donor and acceptor sites, D4, A5, A7, and A8, involved in regulating the generation of multiple HIV RNA transcripts proved to be effective for trans-splicing mediated selective killing of HIV-infected cells, within which individual constructs targeting D4 and A8 were the most efficient.

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HIV-1 infection of hematopoietic progenitor cells in vivo in humanized mice

Abstract: Key Points Some CD34+CD38+ intermediate hematopoietic progenitor cells express HIV-1 entry receptors and are susceptible to direct infection by HIV. Blood progenitors from HIV-exposed, humanized BLT mice show impaired hematopoietic potential and give rise to progeny that harbor provirus.

Cited by 45 publications

References 37 publications

Plasmacytoid dendritic cells promote HIV-1–induced group 3 innate lymphoid cell depletion

Plasmacytoid dendritic cells promote HIV-1–induced group 3 innate lymphoid cell depletion

Targeting HIV latency: resting memory T cells, hematopoietic progenitor cells and future directions

Expression of Herpes Simplex Virus Thymidine Kinase/Ganciclovir by RNA Trans-Splicing Induces Selective Killing of HIV-Producing Cells

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