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Journal of Virology, March 2008, p. 3078-3089, Vol. 82, No. 6
0022-538X/08/$08.00+0     doi:10.1128/JVI.01812-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

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{triangledown}

Aviva Joseph,1,2 Jian Hua Zheng,1 Antonia Follenzi,3 Teresa DiLorenzo,2,4 Kaori Sango,2 Jaime Hyman,2 Ken Chen,5 Alicja Piechocka-Trocha,6,7 Christian Brander,6,7 Erik Hooijberg,8 Dario A. Vignali,9 Bruce D. Walker,6,7 and Harris Goldstein1,2*

Departments of Pediatrics,1 Microbiology & Immunology,2 Pathology,3 Medicine,4 Developmental & Molecular Biology, Albert Einstein College of Medicine, Bronx, New York, 10461,5 Partners AIDS Research Center, Massachusetts General Hospital and Division of AIDS, Harvard Medical School, Boston, Massachusetts 02115,6 Howard Hughes Medical Institute, Chevy Chase, Maryland 20185,7 Department of Pathology, VU University Medical Center, de Boelelaan 1117, NL-1081 HV Amsterdam, The Netherlands,8 Department of Immunology, St. Jude Children's Research Hospital, 332 N. Lauderdale, Memphis, Tennessee 381059

Received 17 August 2007/ Accepted 24 December 2007

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) {alpha} 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 {alpha} 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.

* Corresponding author. Mailing address: Albert Einstein College of Medicine, Forchheimer Building, Room 408, 1300 Morris Park Ave., Bronx, NY 10461. Phone: (718) 430-2156. Fax: (718) 430-8972. E-mail: hgoldste{at}aecom.yu.edu

{triangledown} Published ahead of print on 9 January 2008.

Journal of Virology, March 2008, p. 3078-3089, Vol. 82, No. 6
0022-538X/08/$08.00+0     doi:10.1128/JVI.01812-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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