Gene therapy for human immunodeficiency virus infection in the humanized SCID mouse model.
BACKGROUND
The humanized SCID mouse model is an attractive tool for testing gene therapy to combat human immunodeficiency virus infection in vivo.


OBJECTIVE
To devise a more specific gene therapy directed against HIV, replacing the formerly used interferon with either soluble CD4 molecule immunoadhesin (sCD4-IgG) and/or anti-gp41 monoclonal antibody (2F5), or HIV-negative transdominants genes (Tat, Rev).


METHODS
Human monocytoid cell line (U937) was transfected with IFN alpha, beta or gamma genes. 3T3 murine fibroblastic cell line was transfected with sCD4-IgG or 2F5, or both genes, and a human T4 cell line (CEM) was grafted to SCID mice. Negative transdominant genes (Tat, Rev or both) were also transduced in CEM T cell line. Animals were then challenged with HIV-1, Viral load was followed.


RESULTS
IFN alpha or beta were potent anti-HIV, reducing viral load in vivo and inhibiting reverse transcriptase activity in human-removed cells from animals. sCD4-IgG immunoadhesin and gp41 monoclonal antibody resulted in a dramatic reduction of HIV-1 cellular and plasmatic viral load in humanized SCID mice. The simultaneous introduction of negative Tat and Rev genes resulted in a synergistic inhibition of HIV-1 replication in vivo.


CONCLUSIONS
Despite the marked reduction of HIV-1 propagation by IFN genes or by negative Tat and Rev transdominants, the gene therapy using soluble CD4 immunoadhesin or anti-gp41 was a more efficient preventive treatment against HIV infection.
Touraine
Jean-Louis
JL
Immunology Laboratory for Transplantation and Immunovirology, Edouard Herriot Hospital, Lyon, France. jean-louis.touraine@chu-lyon.fr
Sanhadji
Kamel
K
Sembeil
Rachel
R
D000818:Animals; D016860:CD4 Immunoadhesins / Q000627:therapeutic use*; D004195:Disease Models, Animal; D015757:Genes, rev; D015756:Genes, tat; D015316:Genetic Therapy / Q000379:methods*; D015658:HIV Infections / Q000628:therapy*; D006801:Humans; D007372:Interferons / Q000235:genetics* / Q000627:therapeutic use; D051379:Mice; D016513:Mice, SCID; D012194:RNA-Directed DNA Polymerase / Q000378:metabolism; D014170:Transformation, Genetic / Q000235:genetics
D016860:CD4 Immunoadhesins; D007372:Interferons; D012194:RNA-Directed DNA Polymerase