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.
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.
Joseph
Aviva
A
Albert Einstein College of Medicine, Forchheimer Building, Room 408, 1300 Morris Park Ave., Bronx, NY 10461, USA.
Zheng
Jian Hua
JH
Follenzi
Antonia
A
Dilorenzo
Teresa
T
Sango
Kaori
K
Hyman
Jaime
J
Chen
Ken
K
Piechocka-Trocha
Alicja
A
Brander
Christian
C
Hooijberg
Erik
E
Vignali
Dario A
DA
Walker
Bruce D
BD
Goldstein
Harris
H
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*
D011948:Receptors, Antigen, T-Cell