HIV-specific CD8+ T cells from HIV+ individuals receiving HAART can be expanded ex vivo to augment systemic and mucosal immunity in vivo

Chapuis, Aude G.; Casper, Corey; Kuntz, Steve; Zhu, Jia; Tjernlund, Annelie; Diem, Kurt; Turtle, Cameron J.; Cigal, Melinda; Velez, Roxanne; Riddell, Stanley R.; Corey, Lawrence; Greenberg, Philip D.

doi:10.1182/blood-2010-11-320226

Cited by 39 publications

(28 citation statements)

References 51 publications

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“…Despite decades of effort, clinical progress in the treatment of HIV-1 infection remains limited principally by high viral mutation rates and the persistence of latently infected cells (51)(52)(53). In the present study, we combined an extracellular domain derived from the scFv of the HIV-1 bNAb VRC01 and a third-generation CAR moiety to develop novel MHC-independent, anti-HIV-1 VC-CAR-T cells.…”

Section: Discussionmentioning

confidence: 99%

Chimeric Antigen Receptor T Cells Guided by the Single-Chain Fv of a Broadly Neutralizing Antibody Specifically and Effectively Eradicate Virus Reactivated from Latency in CD4 ⁺ T Lymphocytes Isolated from HIV-1-Infected Individuals Receiving Suppressive Combined Antiretroviral Therapy

Liu

Zou

et al. 2016

J Virol

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Despite the advent of combined antiretroviral therapy (cART), the persistence of viral reservoirs remains a major barrier to curing human immunodeficiency virus type 1 (HIV-1) infection. Recently, the shock and kill strategy, by which such reservoirs are eradicated following reactivation of latent HIV-1 by latency-reversing agents (LRAs), has been extensively practiced. It is important to reestablish virus-specific and reliable immune surveillance to eradicate the reactivated virus-harboring cells. In this report, we attempted to reach this goal by using newly developed chimeric antigen receptor (CAR)-T cell technology. To generate anti-HIV-1 CAR-T cells, we connected the single-chain variable fragment of the broadly neutralizing HIV-1-specific antibody VRC01 to a third-generation CAR moiety as the extracellular and intracellular domains and subsequently transduced this into primary CD8 ؉ T lymphocytes. We demonstrated that the resulting VC-CAR-T cells induced T cell-mediated cytolysis of cells expressing HIV-1 Env proteins and significantly inhibited HIV-1 rebound after removal of antiviral inhibitors in a viral infectivity model in cell culture that mimics the termination of the cART in the clinic. Importantly, the VC-CAR-T cells also effectively induced the cytolysis of LRA-reactivated HIV-1-infected CD4؉ T lymphocytes isolated from infected individuals receiving suppressive cART. Our data demonstrate that the special features of genetically engineered CAR-T cells make them a particularly suitable candidate for therapeutic application in efforts to reach a functional HIV cure. IMPORTANCEThe presence of latently infected cells remains a key obstacle to the development of a functional HIV-1 cure. Reactivation of dormant viruses is possible with latency-reversing agents, but the effectiveness of these compounds and the subsequent immune response require optimization if the eradication of HIV-1-infected cells is to be achieved. Here, we describe the use of a chimeric antigen receptor, comprised of T cell activation domains and a broadly neutralizing antibody, VRC01, targeting HIV-1 to treat the infected cells. T cells expressing this construct exerted specific cytotoxic activity against wild-type HIV-1-infected cells, resulting in a dramatic reduction in viral rebound in vitro, and showed persistent effectiveness against reactivated latently infected T lymphocytes from HIV-1 patients receiving combined antiretroviral therapy. The methods used in this study constitute an improvement over existing CD4-based CAR-T technology and offer a promising approach to HIV-1 immunotherapy. HIV-1 replication can be efficiently suppressed with combined antiretroviral therapy (cART). However, treatment must be maintained throughout the lifetime of the patient, as this virus can persist in a stable latent reservoir, constituting a major barrier to the establishment of an HIV-1 cure. To date, many strategies have been proposed for the eradication of HIV-1 reservoirs (1-3). Recent efforts have focused on the reactivation of ...

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Section: Discussionmentioning

confidence: 99%

Chimeric Antigen Receptor T Cells Guided by the Single-Chain Fv of a Broadly Neutralizing Antibody Specifically and Effectively Eradicate Virus Reactivated from Latency in CD4 ⁺ T Lymphocytes Isolated from HIV-1-Infected Individuals Receiving Suppressive Combined Antiretroviral Therapy

Liu

Zou

et al. 2016

J Virol

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“…One potential strategy to clear persistently infected cells is the adoptive transfer of HIV-1-specific CTLs 152 . In a primary cell model of latency, Gag-stimulated CTLs are much more effective at clearing reactivated HIV-1-infected cells than freshly isolated CD8 + T cells 144 .…”

Section: Clearing Persistently Infected Cellsmentioning

confidence: 99%

Eradicating HIV-1 infection: seeking to clear a persistent pathogen

et al. 2014

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Effective antiretroviral therapy (ART) blunts viraemia, which enables HIV-1-infected individuals to control infection and live long, productive lives. However, HIV-1 infection remains incurable owing to the persistence of a viral reservoir that harbours integrated provirus within host cellular DNA. This latent infection is unaffected by ART and hidden from the immune system. Recent studies have focused on the development of therapies to disrupt latency. These efforts unmasked residual viral genomes and highlighted the need to enable the clearance of latently infected cells, perhaps via old and new strategies that improve the HIV-1-specific immune response. In this Review, we explore new approaches to eradicate established HIV-1 infection and avoid the burden of lifelong ART.

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“…Enriching for T cells with a memory phenotype therefore may provide ex vivo expanded T cell products with a greater potential for persistence. A group in Seattle infused 7 participants with autologous HIV-specific CD8+ T cells derived from the central memory subset (CD28+, CD62L), resulting in the clones persisting for up to 84 days post-infusion [75]. Significantly, these cells localized to the rectal mucosa and T cells maintained their expression of CD28, upregulated CD62L, and expanded in vivo .…”

Section: Gene Editing Strategiesmentioning

confidence: 99%

T-cell therapies for HIV: Preclinical successes and current clinical strategies

et al. 2016

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While antiretroviral therapy (ART) has been successful in controlling HIV infection, it does not provide a permanent cure solution, requires lifelong treatment, and HIV+ individuals are left with social dysmorphias such as stigma [1, 2]. The recent application of T cells to treat cancer and viral reactivations post-transplant offers a potential strategy to control HIV infection. It is known that naturally occurring HIV-specific T cells can inhibit HIV initially, but this response is not sustained in the majority of people living with HIV (PLWH). Genetically modifying T cells to target HIV, resist infection, and persist in the immunosuppressive environment found in chronically infected HIV+ individuals might provide a therapeutic solution for HIV. This review focuses on successful pre-clinical studies and current clinical strategies using T cell therapy to control HIV infection and mediate a functional cure solution.

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HIV-specific CD8+ T cells from HIV+ individuals receiving HAART can be expanded ex vivo to augment systemic and mucosal immunity in vivo

Cited by 39 publications

References 51 publications

Chimeric Antigen Receptor T Cells Guided by the Single-Chain Fv of a Broadly Neutralizing Antibody Specifically and Effectively Eradicate Virus Reactivated from Latency in CD4 ⁺ T Lymphocytes Isolated from HIV-1-Infected Individuals Receiving Suppressive Combined Antiretroviral Therapy

Chimeric Antigen Receptor T Cells Guided by the Single-Chain Fv of a Broadly Neutralizing Antibody Specifically and Effectively Eradicate Virus Reactivated from Latency in CD4 ⁺ T Lymphocytes Isolated from HIV-1-Infected Individuals Receiving Suppressive Combined Antiretroviral Therapy

Eradicating HIV-1 infection: seeking to clear a persistent pathogen

T-cell therapies for HIV: Preclinical successes and current clinical strategies

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HIV-specific CD8+ T cells from HIV+ individuals receiving HAART can be expanded ex vivo to augment systemic and mucosal immunity in vivo

Cited by 39 publications

References 51 publications

Chimeric Antigen Receptor T Cells Guided by the Single-Chain Fv of a Broadly Neutralizing Antibody Specifically and Effectively Eradicate Virus Reactivated from Latency in CD4 + T Lymphocytes Isolated from HIV-1-Infected Individuals Receiving Suppressive Combined Antiretroviral Therapy

Chimeric Antigen Receptor T Cells Guided by the Single-Chain Fv of a Broadly Neutralizing Antibody Specifically and Effectively Eradicate Virus Reactivated from Latency in CD4 + T Lymphocytes Isolated from HIV-1-Infected Individuals Receiving Suppressive Combined Antiretroviral Therapy

Eradicating HIV-1 infection: seeking to clear a persistent pathogen

T-cell therapies for HIV: Preclinical successes and current clinical strategies

Contact Info

Product

Resources

About

Chimeric Antigen Receptor T Cells Guided by the Single-Chain Fv of a Broadly Neutralizing Antibody Specifically and Effectively Eradicate Virus Reactivated from Latency in CD4 ⁺ T Lymphocytes Isolated from HIV-1-Infected Individuals Receiving Suppressive Combined Antiretroviral Therapy

Chimeric Antigen Receptor T Cells Guided by the Single-Chain Fv of a Broadly Neutralizing Antibody Specifically and Effectively Eradicate Virus Reactivated from Latency in CD4 ⁺ T Lymphocytes Isolated from HIV-1-Infected Individuals Receiving Suppressive Combined Antiretroviral Therapy