Lentiviral vectors encoding human immunodeficiency virus type 1 (HIV-1)-specific T-cell receptor genes efficiently convert peripheral blood CD8 T lymphocytes into cytotoxic T lymphocytes with potent in vitro and in vivo HIV-1-specific inhibitory activity

Aviva Joseph, Hua Zheng Jian, Antonia Follenzi, Teresa P. DiLorenzo, Kaori Sango, Jaime Hyman, Ken Chen, Alicja Piechocka-Trocha, Christian Brander, Erik Hooijberg, Dario A. Vignali, Bruce D. Walker, Harris Goldstein

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Abstract

The human immunodeficiency virus type 1 (HIV-1)-specific CD8 cytotoxic T-lymphocyte (CTL) response plays a critical role in controlling HIV-1 replication. Augmenting this response should enhance control of HIV-1 replication and stabilize or improve the clinical course of the disease. Although cytomegalovirus (CMV) or Epstein-Barr virus (EBV) infection in immunocompromised patients can be treated by adoptive transfer of ex vivo-expanded CMV- or EBV-specific CTLs, adoptive transfer of ex vivo-expanded, autologous HIV-1-specific CTLs had minimal effects on HIV-1 replication, likely a consequence of the inherently compromised qualitative function of HIV-1-specific CTLs derived from HIV-1-infected individuals. We hypothesized that this limitation could be circumvented by using as an alternative source of HIV-1-specific CTLs, autologous peripheral CD8+ T lymphocytes whose antigen specificity is redirected by transduction with lentiviral vectors encoding HIV-1-specific T-cell receptor (TCR) α and β chains, an approach used successfully in cancer therapy. To efficiently convert peripheral CD8 lymphocytes into HIV-1-specific CTLs that potently suppress in vivo HIV-1 replication, we constructed lentiviral vectors encoding the HIV-1-specific TCR α and TCR β chains cloned from a CTL clone specific for an HIV Gag epitope, SL9, as a single transcript linked with a self-cleaving peptide. We demonstrated that transduction with this lentiviral vector efficiently converted primary human CD8 lymphocytes into HIV-1-specific CTLs with potent in vitro and in vivo HIV-1-specific activity. Using lentiviral vectors encoding an HIV-1-specific TCR to transform peripheral CD8 lymphocytes into HIV-1-specific CTLs with defined specificities represents a new immunotherapeutic approach to augment the HIV-1-specific immunity of infected patients.

Original languageEnglish (US)
Pages (from-to)3078-3089
Number of pages12
JournalJournal of Virology
Volume82
Issue number6
DOIs
StatePublished - Mar 2008

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T-Cell Receptor Genes
cytotoxic T-lymphocytes
Cytotoxic T-Lymphocytes
Human immunodeficiency virus 1
HIV-1
T-lymphocytes
T-Lymphocytes
receptors
blood
genes
Virus Replication
T-Cell Antigen Receptor
Cytomegalovirus
Human herpesvirus 4
In Vitro Techniques
lymphocytes
Adoptive Transfer
Lymphocytes
lymphocyte antigens
Epstein-Barr Virus Infections

ASJC Scopus subject areas

  • Immunology

Cite this

Lentiviral vectors encoding human immunodeficiency virus type 1 (HIV-1)-specific T-cell receptor genes efficiently convert peripheral blood CD8 T lymphocytes into cytotoxic T lymphocytes with potent in vitro and in vivo HIV-1-specific inhibitory activity. / Joseph, Aviva; Jian, Hua Zheng; Follenzi, Antonia; DiLorenzo, Teresa P.; Sango, Kaori; Hyman, Jaime; Chen, Ken; Piechocka-Trocha, Alicja; Brander, Christian; Hooijberg, Erik; Vignali, Dario A.; Walker, Bruce D.; Goldstein, Harris.

In: Journal of Virology, Vol. 82, No. 6, 03.2008, p. 3078-3089.

Research output: Contribution to journalArticle

Joseph, Aviva ; Jian, Hua Zheng ; Follenzi, Antonia ; DiLorenzo, Teresa P. ; Sango, Kaori ; Hyman, Jaime ; Chen, Ken ; Piechocka-Trocha, Alicja ; Brander, Christian ; Hooijberg, Erik ; Vignali, Dario A. ; Walker, Bruce D. ; Goldstein, Harris. / Lentiviral vectors encoding human immunodeficiency virus type 1 (HIV-1)-specific T-cell receptor genes efficiently convert peripheral blood CD8 T lymphocytes into cytotoxic T lymphocytes with potent in vitro and in vivo HIV-1-specific inhibitory activity. In: Journal of Virology. 2008 ; Vol. 82, No. 6. pp. 3078-3089.
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abstract = "The human immunodeficiency virus type 1 (HIV-1)-specific CD8 cytotoxic T-lymphocyte (CTL) response plays a critical role in controlling HIV-1 replication. Augmenting this response should enhance control of HIV-1 replication and stabilize or improve the clinical course of the disease. Although cytomegalovirus (CMV) or Epstein-Barr virus (EBV) infection in immunocompromised patients can be treated by adoptive transfer of ex vivo-expanded CMV- or EBV-specific CTLs, adoptive transfer of ex vivo-expanded, autologous HIV-1-specific CTLs had minimal effects on HIV-1 replication, likely a consequence of the inherently compromised qualitative function of HIV-1-specific CTLs derived from HIV-1-infected individuals. We hypothesized that this limitation could be circumvented by using as an alternative source of HIV-1-specific CTLs, autologous peripheral CD8+ T lymphocytes whose antigen specificity is redirected by transduction with lentiviral vectors encoding HIV-1-specific T-cell receptor (TCR) α and β chains, an approach used successfully in cancer therapy. To efficiently convert peripheral CD8 lymphocytes into HIV-1-specific CTLs that potently suppress in vivo HIV-1 replication, we constructed lentiviral vectors encoding the HIV-1-specific TCR α and TCR β chains cloned from a CTL clone specific for an HIV Gag epitope, SL9, as a single transcript linked with a self-cleaving peptide. We demonstrated that transduction with this lentiviral vector efficiently converted primary human CD8 lymphocytes into HIV-1-specific CTLs with potent in vitro and in vivo HIV-1-specific activity. Using lentiviral vectors encoding an HIV-1-specific TCR to transform peripheral CD8 lymphocytes into HIV-1-specific CTLs with defined specificities represents a new immunotherapeutic approach to augment the HIV-1-specific immunity of infected patients.",
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AU - Follenzi, Antonia

AU - DiLorenzo, Teresa P.

AU - Sango, Kaori

AU - Hyman, Jaime

AU - Chen, Ken

AU - Piechocka-Trocha, Alicja

AU - Brander, Christian

AU - Hooijberg, Erik

AU - Vignali, Dario A.

AU - Walker, Bruce D.

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