title: 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.
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) alpha and beta 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 beta 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.
authors.affiliation: Albert Einstein College of Medicine, Forchheimer Building, Room 408, 1300 Morris Park Ave., Bronx, NY 10461, USA.
authors.forename: Aviva
authors.initials: A
authors.lastname: Joseph
authors.forename: Jian Hua
authors.initials: JH
authors.lastname: Zheng
authors.forename: Antonia
authors.initials: A
authors.lastname: Follenzi
authors.forename: Teresa
authors.initials: T
authors.lastname: Dilorenzo
authors.forename: Kaori
authors.initials: K
authors.lastname: Sango
authors.forename: Jaime
authors.initials: J
authors.lastname: Hyman
authors.forename: Ken
authors.initials: K
authors.lastname: Chen
authors.forename: Alicja
authors.initials: A
authors.lastname: Piechocka-Trocha
authors.forename: Christian
authors.initials: C
authors.lastname: Brander
authors.forename: Erik
authors.initials: E
authors.lastname: Hooijberg
authors.forename: Dario A
authors.initials: DA
authors.lastname: Vignali
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Walker
authors.forename: Harris
authors.initials: H
authors.lastname: Goldstein
mesh_terms: D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002478:Cells, Cultured; D003001:Cloning, Molecular; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005818:Genetic Engineering; D005822:Genetic Vectors; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D011948:Receptors, Antigen, T-Cell / Q000235:genetics*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
chemical_list: D011948:Receptors, Antigen, T-Cell