Use of a lentiviral flap vector for induction of CTL immunity against melanoma. Perspectives for immunotherapy.
BACKGROUND
A central triple-stranded DNA structure created during HIV-1 reverse transcription, the central flap, acts as a cis-active nuclear import determinant of the HIV-1 DNA genome. Insertion of the sequences responsible for formation of the central DNA flap into an HIV-1-derived vector strongly enhances its transduction efficiency.


METHODS
HIV-1 vectors with or without inclusion of the DNA flap and encoding the same melanoma polyepitope were constructed to transduce dendritic cells (DCs) and to evaluate their capacity for induction of melanoma-specific cytotoxic T-lymphocyte (CTL) responses ex vivo and in vivo.


RESULTS
HIV-1 vectors including the DNA flap transduced up to 100% of immature mouse and human DCs. Inoculation of HLA-A2.1 transgenic mice with this flap vector elicited vigorous and multi-specific long-term anti-melanoma CTL responses, whereas the parental vector lacking the flap sequence was less efficient. Furthermore, human DCs transduced ex vivo with the recombinant DNA flap vector displayed efficient multi-specific primary human CTL responses against melanoma.


CONCLUSIONS
Lentiviral vectors including the DNA flap should be powerful tools both for active immunization and for the ex vivo priming of CTL for tumor immunotherapy.
Firat
Hüseyin
H
Unité d'Immunité Cellulaire Antivirale, CNRS, URA 1923, lbis rue de l'Internationale, BP60-91002 Evry Cédex, France. firat@genethon.fr
Zennou
Véronique
V
Garcia-Pons
Francisco
F
Ginhoux
Florent
F
Cochet
Madeleine
M
Danos
Olivier
O
Lemonnier
François A
FA
Langlade-Demoyen
Pierre
P
Charneau
Pierre
P
D000818:Animals; D017951:Antigen Presentation; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000276:immunology*; D005786:Gene Expression Regulation; D005822:Genetic Vectors; D006678:HIV; D006801:Humans; D007167:Immunotherapy; D008545:Melanoma / Q000276:immunology* / Q000628:therapy; D051379:Mice; D008822:Mice, Transgenic; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014161:Transduction, Genetic / Q000379:methods*
D000951:Antigens, Neoplasm