Autocrine interferon-β synthesis for gene therapy of HIV infection

Abstract

To explore the possibility of gene therapy of HIV infection based on the multiple antiretroviral activities of interferon (IFN)-beta. We introduced into HIV target cells an IFN-beta gene placed under an expression control ensuring a low and constitutive expression, sufficient to confer a permanent antiviral state without impeding normal cell function. We transformed, with an efficacy ranging from 20-55%, peripheral blood lymphocytes (PBL) derived from healthy, seronegative donors, and from asymptomatic HIV-infected individuals by the HMB-KbHuIFN beta retroviral vector carrying the human IFN-beta coding sequence driven by a fragment of the murine H-2Kb gene promoter. The replication rate of the IFN-beta-expressing cells was no different from that of untransformed controls during the 21-day period of in vitro observation. When IFN-beta-transformed, purified CD4+ lymphocytes from healthy donors were HIV-1LAI-infected, virus replication was inhibited and most of the cells survived, in contrast to untransformed CD4+ cells which were all destroyed 12 days after infection. Protection of CD4+ cells from the same donors was also observed in suspensions of IFN-beta-transformed total PBL that were infected with HIV-1LAI. In IFN-beta-transformed PBL from four HIV-infected donors, endogenous HIV replication was decreased and 28-69% of the CD4+ cells survived at the end of the 21 days in culture. In the untransformed control PBL suspensions, all CD4+ cells were destroyed. In long-term experiments, HIV-infected, IFN-beta-transformed cell populations of the lymphocytic CEM and the promonocytic U937 line were kept in culture for 60 days, during which time they remained resistant to HIV infection. These results indicate that further exploration of autocrine IFN-beta production for somatic cell gene therapy of HIV infection is warranted.