AEGiS-13IAC: Gene therapy of AIDS based on constitutive expression of IFN-beta: experimental approach in macaques chronically infected with a pathogenic SIV.

13th International AIDS Conference

Durban, South Africa - July 9-July 14, 2000

Gene therapy of AIDS based on constitutive expression of IFN-beta: experimental approach in macaques chronically infected with a pathogenic SIV.

Int Conf AIDS 2000 Jul 9-14; 13:(abstract no. MoOrA103)

Gay W, Lauret E, Largherd J, Vaslin B, De Maeyer E, Dormont D, Le Grand R, Lauret E
W. Gay, CEA Service de Neurovirologie DSV/DRM/SNV, 60 68 Avenue de la Division Leclerc, Fontenay Aux Roses 92265 BP6, France, Tel.: +33 1 146 549 469, Fax: +33 1 146 647 726, E-mail: wgaylen@aol.com

OBJECTIVES: To evaluate, in the model of of macaques infected with a pathogenic SIVmac251, a gene therapy strategy based on the constitutive and low expression of interferon b . We have previously reported that this strategy protects PBL from infection in vitro with SIV and that transduced cells ex vivo, persisted in the peripheral blood after injection to healthy or SIV infected macaques. Material and

METHODS: Cynomolgus macaques were infected from more than a year with a pathogenic primary isolate of Simac251. At the beginning of the experiment, all the animals were asymptomatic, positive for virus detection in PBMC, exhibited low plasma viral load and circulating CD4+ T lymphocytes were higher than 700 cells/m l. The retroviral vector used was derived from MuMLV and allowed the constitutive expression of macaque IFN-b under the control of the murine H2-KB promoter. A similar construct expressing a biologically inactive deleted form of IFN-b was used as control. ConA activated monkey PBL were transduced ex vivo then injected to macaques. Groups of three animals received cells expressing the transduced INF-b , the control vector or both. Virological and immunological parameters of SIVmac251 infection were determined.

RESULTS: After injection of autoloqous transduced cells, the therapeutic gene was evidenced in PBMC of all the animals with copy numbers varying between 1000 and 70 per 106 cells. Within the days following injection, a transient decrease of CD4+ circulating T cells, associated with a transient increase of cellular and plasma viremia was noticed in most of the animals, regardless the retroviral construct used. In the long term, injection of cells with the vector expressing the INF-b , did not prevent from the progressive CD4+ cells decrease which characterize SIV infection.

CONCLUSION: Injection of transduced cells may be accompanied with transient adverse effects. Low percentages of circulating transduced cells did not prevent macaques from progression to disease.

Keywords: AEGIS, SIV, Macaca, Simian Acquired Immunodeficiency Syndrome, Gene Therapy, Acquired Immunodeficiency Syndrome, Viral Load, CD4-Positive T-Lymphocytes, Retroviridae, Genetic Vectors, Viremia, T-Lymphocytes, Animal, In Vitro, genetics
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MoOrA103