Genetically Modified Hematopoietic Stem Cell Transplantation for HIV-1–infected Patients: Can We Achieve a Cure?

Younan, Patrick; Kowalski, John P.; Kiem, Hans Peter

doi:10.1038/mt.2013.264

Cited by 18 publications

(11 citation statements)

References 79 publications

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“…Moreover, in light of recent data illustrating efficient in vitro genome editing using a mixture of Cas9/gRNA and DNA (39)(40)(41)(42), one may explore various systems for delivery of Cas9/LTR-gRNA via various routes for immunizing high-risk subjects. Once advanced, one may use gene therapies (viral vector and nanoparticle) and transplantation of autologous Cas9/gRNA-modified bone marrow stem/progenitor cells (43,44) or inducible pluripotent stem cells for eradicating HIV-1 infection.…”

Section: Discussionmentioning

confidence: 99%

RNA-directed gene editing specifically eradicates latent and prevents new HIV-1 infection

Kaminski

Yang

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

482

475

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Significance For more than three decades since the discovery of HIV-1, AIDS remains a major public health problem affecting greater than 35.3 million people worldwide. Current antiretroviral therapy has failed to eradicate HIV-1, partly due to the persistence of viral reservoirs. RNA-guided HIV-1 genome cleavage by the Cas9 technology has shown promising efficacy in disrupting the HIV-1 genome in latently infected cells, suppressing viral gene expression and replication, and immunizing uninfected cells against HIV-1 infection. These properties may provide a viable path toward a permanent cure for AIDS, and provide a means to vaccinate against other pathogenic viruses. Given the ease and rapidity of Cas9/guide RNA development, personalized therapies for individual patients with HIV-1 variants can be developed instantly.

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Section: Discussionmentioning

confidence: 99%

RNA-directed gene editing specifically eradicates latent and prevents new HIV-1 infection

Kaminski

Yang

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

482

475

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“…CD34 + HSCs), which give rise to multiple infection-susceptible cell types. 15,16 To date, several Phase I/II clinical trials have been conducted in HIV-1 infected patients following infusion of genetically modified CD4 + T-cells or CD34 + HSCs. (reviewed in reference 17 ).…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Lentivirus-mediated Gene Transfer in Hematopoietic Stem Cells Is Impaired in SHIV-infected, ART-treated Nonhuman Primates

Younan

Peterson

Polacino³

et al. 2015

Molecular Therapy

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Recent studies have demonstrated that genetically modified hematopoietic stem cells (HSCs) can reduce HIV viremia. We have developed an HIV/AIDS-patient model in Simian/human immunodeficiency virus (SHIV)-infected pigtailed macaques that are stably suppressed on antiretroviral therapy (ART: raltegravir, emtricitabine and tenofovir). Following SHIV infection and ART, animals undergo autologous HSC transplantation (HSCT) with lentivirally transduced cluster of differentiation (CD)34(+) cells expressing the mC46 anti-HIV fusion protein. We show that SHIV(+), ART-treated animals had very low gene marking levels after HSCT. Pretransduction CD34(+) cells contained detectable levels of all three ART drugs, likely contributing to the low gene transfer efficiency. Following HSCT recovery and the cessation of ART, plasma viremia rebounded, indicating that myeloablative total body irradiation cannot completely eliminate viral reservoirs after autologous HSCT. The kinetics of recovery following autologous HSCT in SHIV(+), ART-treated macaques paralleled those observed following transplantation of control animals. However, T-cell subset analyses demonstrated a high percentage of C-C chemokine receptor 5 (CCR5)-expressing CD4(+) T-cells after HSCT. These data suggest that an extended ART interruption time may be required for more efficient lentiviral transduction. To avoid complications associated with ART interruption in the context of high percentages of CD4(+)CCR5(+)T-cells after HSCT, the use of vector systems not impaired by the presence of residual ART may also be beneficial.

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“…The successful treatment of the ''Berlin patient'' with CD34 + hematopoietic stem cells (HSCs) from a CCR5D32 homozygous individual 1,2 has provided hope for a cure. Although CCR5targeting strategies have been widely studied and tested, [3][4][5] the implementation of targeting CCR5 alone has its limitations as it is likely to be effective only in patients exclusively harboring a CCR5tropic virus. This caveat will greatly limit the applicability of this approach to generalized infected populations.…”

Section: Introductionmentioning

confidence: 99%

Conditional Cytotoxic Anti-HIV Gene Therapy for Selectable Cell Modification

Garg

Joshi

2016

Human Gene Therapy

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Gene therapy remains one of the potential strategies to achieve a cure for HIV infection. One of the major limitations of anti-HIV gene therapy concerns recovering an adequate number of modified cells to generate an HIV-proof immune system. Our study addresses this issue by developing a methodology that can mark conditional vector-transformed cells for selection and subsequently target HIV-infected cells for elimination by treatment with ganciclovir (GCV). We used the herpes simplex virus thymidine kinase (TK) mutant SR39, which is highly potent at killing cells at low GCV concentrations. This gene was cloned into a conditional HIV vector, pNL-GFPRRESA, which expresses the gene of interest as well as green fluorescent protein (GFP) in the presence of HIV Tat protein. We show here that TK-SR39 was more potent that wild-type TK (TK-WT) at eliminating infected cells at lower concentrations of GCV. As the vector expresses GFP in the presence of Tat, transient expression of Tat either by Tat RNA transfection or transduction by a nonintegrating lentiviral (NIL) vector marked the cells with GFP for selection. In cells selected by this strategy, TK-SR39 was more potent at limiting virus replication than TK-WT. Finally, in Jurkat cells modified and selected by this approach, infection with CXCR4-tropic Lai virus could be suppressed by treatment with GCV. GCV treatment limited the number of HIV-infected cells, virus production, as well as virus-induced cytopathic effects in this model. We provide proof of principle that TK-SR39 in a conditional HIV vector can provide a safe and effective anti-HIV strategy.

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Genetically Modified Hematopoietic Stem Cell Transplantation for HIV-1–infected Patients: Can We Achieve a Cure?

Cited by 18 publications

References 79 publications

RNA-directed gene editing specifically eradicates latent and prevents new HIV-1 infection

RNA-directed gene editing specifically eradicates latent and prevents new HIV-1 infection

Lentivirus-mediated Gene Transfer in Hematopoietic Stem Cells Is Impaired in SHIV-infected, ART-treated Nonhuman Primates

Conditional Cytotoxic Anti-HIV Gene Therapy for Selectable Cell Modification

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