[In vitro and in vivo inhibition of HIV1 replication by retroviral transfer of interferon alpha, beta, or gamma genes: application to gene therapy of AIDS].
Somatic gene therapy is defined as the transfer of a heterologous gene into an organism for the purpose of correcting a genetic defect or providing a new therapeutic function to the target cell and thus inducing a cure or improving associated symptoms. While encouraging results have been generated by recent clinical evaluation of combination of anti-viral drugs, Aids still constitute an obvious candidate among the infectious diseases which might be treated by gene therapy. We have therefore chosen to develop and evaluate a gene therapy strategy based on the transfer into human target cells of HIV1-inducible interferon (IFN) alpha, beta or gamma genes. In a preliminary study, myeloïd U937 cell lines transfected with expression vectors containing the IFN alpha, beta or gamma genes under the control of the long terminal repeat (LTR) sequences of HIV1 were shown to be strongly resistant against an in vitro and in vivo (in HIV1 challenged SCID mice model) HIV1 infection. This cellular resistance was correlated with a strong induction of transgenic IFN synthesis and for IFN gamma, with a defect of HIV particles maturation. Secondly, construction and production of high titer retroviral vectors containing Tat-inducible IFN genes allowed efficient transduction of lymphoïd cell lines and human primary lymphocytes. These transduced cells were shown to be highly resistant against laboratory and primary HIV isolates. Taken together, our in vitro and in vivo results suggest that HIV1 inducible IFN gene therapy can be beneficial to HIV-infected individuals provided the fact that methods are developed that allow the efficient transduction of human hematopoïetic stem cells.
Leissner
P
P
Transgène SA, Strasbourg.
Calenda
V
V
Marigliano
M
M
Sanhadji
K
K
Touraine
J L
JL
Pavirani
A
A
Mehtali
M
M
D000163:Acquired Immunodeficiency Syndrome / Q000628:therapy*; D000818:Animals; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D016325:HIV Long Terminal Repeat; D015497:HIV-1 / Q000502:physiology; D006801:Humans; D016898:Interferon-alpha / Q000235:genetics; D016899:Interferon-beta / Q000235:genetics; D007371:Interferon-gamma / Q000235:genetics; D007372:Interferons / Q000235:genetics*; D051379:Mice; D012190:Retroviridae; D014779:Virus Replication
D016898:Interferon-alpha; D016899:Interferon-beta; D007371:Interferon-gamma; D007372:Interferons