Experimental gene therapy: the transfer of Tat-inducible interferon genes protects human cells against HIV-1 challenge in vitro and in vivo in severe combined immunodeficient mice.
OBJECTIVE
To evaluate in vitro and in vivo a strategy for gene therapy for AIDS based on the transfer on interferon (IFN)-alpha, -beta and -gamma genes to human cells.


METHODS
Human U937 promonocytic cells were stably transfected with Tat-inducible IFN expression vectors conferring an antiviral state against infection with HIV.


METHODS
Transfected cells were either infected by HIV-1 in vitro or transplanted into severe combined immunodeficient (SCID) mice for an HIV challenge in vivo.


RESULTS
U937 cell lines stably carrying IFN transgenes under the positive control of the HIV-1 Tat protein were highly resistant to HIV-1 replication in vitro. This antiviral resistance was associated with a strong induction of IFN synthesis immediately following the viral infection. HIV-1 proteins were found to be specifically trapped within the genetically modified cells. In contrast, all IFN-U937 cells permitted full HIV-2 replication. Transfected cells injected into SCID mice and challenged against HIV-1 were strongly resistant to infection when cells were transduced with IFN-alpha of IFN-beta genes. However, IFN-gamma-transfected cells permitted HIV-1 infection in vivo despite the induction of a high level of IFN-gamma secretion. The quantity of proviral DNA was 10(5)-fold lower in IFN-alpha- or IFN-beta-transfected U937 cells collected from these SCID mice than that in non-transfected cells.


CONCLUSIONS
Our results substantiated the validity of a strategy, bases on the transfer of HIV-1-inducible IFN-alpha or IFN-beta genes, to confer antiviral resistance to human cells.
Sanhadji
K
K
Laboratory of Immune Deficiency and INSERM U80, Department of Medicine R.T.H. Laënnec, Lyon, France.
Leissner
P
P
Firouzi
R
R
Pelloquin
F
F
Kehrli
L
L
Marigliano
M
M
Calenda
V
V
Ottmann
M
M
Tardy
J C
JC
Mehtali
M
M
Touraine
J L
JL
D000163:Acquired Immunodeficiency Syndrome / Q000628:therapy*; D000818:Animals; D017690:Cell Transplantation; D004195:Disease Models, Animal; D015696:Gene Products, tat / Q000502:physiology*; D015316:Genetic Therapy; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D016898:Interferon-alpha / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology; D016899:Interferon-beta / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology; D051379:Mice; D016513:Mice, SCID; D014407:Tumor Cells, Cultured; D054322:tat Gene Products, Human Immunodeficiency Virus
D015696:Gene Products, tat; D016898:Interferon-alpha; D054322:tat Gene Products, Human Immunodeficiency Virus; D016899:Interferon-beta; D007371:Interferon-gamma