Low autocrine interferon beta production as a gene therapy approach for AIDS: Infusion of interferon beta-engineered lymphocytes in macaques chronically infected with SIVmac251

BACKGROUND: The aim of this study was to evaluate gene therapy for AIDS based on the transduction of circulating lymphocytes with a retroviral vector giving low levels of constitutive macaque interferon β production in macaques chronically infected with a pathogenic isolate of SIVmac251. RESULTS: Two groups of three animals infected for more than one year with a pathogenic primary isolate of SIVmac251 were included in this study. The macaques received three infusions of their own lymphocytes transduced ex vivo with the construct encoding macaque IFN-β (MaIFN-β or with a vector carrying a version of the MaIFN-β gene with a deletion preventing translation of the mRNA. Cellular or plasma viremia increased transiently following injection in most cases, regardless of the retroviral construct used. Transduced cells were detected only transiently after each infusion, among the peripheral blood mononuclear cells of all the animals, with copy numbers of 10 to 1000 per 10(6 )peripheral mononuclear cells. CONCLUSION: Long-term follow-up indicated that the transitory presence of such a small number of cells producing such small amounts of MaIFN-β did not prevent animals from the progressive decrease in CD4(+ )cell count typical of infection with simian immunodeficiency virus. These results reveal potential pitfalls for future developments of gene therapy strategies of HIV infection

Selective enhancement of emotional, but not motor, learning in monoamine oxidase A-deficient mice

Mice deficient in monoamine oxidase A (MAOA), an enzyme that metabolizes monoamines such as norepinephrine and serotonin, have elevated norepinephrine and serotonin levels in the frontal cortex, hippocampus, and cerebellum, compared with normal wild-type mice. Since monoamines in these areas are critically involved in a variety of behaviors, we examined learning and memory (using emotional and motor tasks) in MAOA mutant mice. The MAOA-deficient mice exhibited significantly enhanced classical fear conditioning (freezing to both tone and contextual stimuli) and step-down inhibitory avoidance learning. In contrast, eyeblink conditioning was normal in these mutant mice. The female MAOA-deficient mice also displayed normal species-typical maternal behaviors (nesting, nursing, and pup retrieval). These results suggest that chronic elevations of monoamines, due to a deletion of the gene encoding MAOA, lead to selective alterations in emotional behavior.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/56225/1/kimPNAS97.pd

Interferon Synthesis in X-Irradiated Animals V. Origin of Mouse Serum Interferon Induced by Polyinosinic-Polycytidylic Acid and Encephalomyocarditis Virus

The radioresistant cell systems producing serum interferon after intravenous administration of polyinosinic-polycytidylic acid [poly(I·C)] or encephalomyocarditis virus in mice were studied in rat-to-mouse radiation chimeras. Interferon induced by poly(I·C) became of donor type within 3 months after grafting of irradiated C3H/He mice with Wistar rat bone marrow cells; this indicated that it was made in cells derived from the hemopoietic system. In contrast, encephalomyocarditis virus-induced interferon remained of recipient type in xenogeneic chimeras up to 3 months after grafting, which indicated that the bulk of this interferon originated from a cell population not derived from the hemopoietic system. To ascertain that the respective radiosensitivities of the systems producing rat interferon in chimeras corresponded to that of normal mice, some rat-to-mouse chimeras were subjected to a second X irradiation 1 month after the first irradiation and restoration. Circulating interferon production was studied 4 days later. As expected, the re-irradiation strongly depressed rat serum interferon production induced by Newcastle disease virus but had no effect on rat interferon synthesis induced by poly (I·C). These results point to a macrophage origin for the bulk of poly(I·C)-induced circulating interferon

INTERFERON SYNTHESIS IN X-IRRADIATED ANIMALS, IV. DONOR-TYPE SERUM INTERFERONS IN RAT-TO-MOUSE RADIATION CHIMERAS INJECTED WITH NEW CASTLE DISEASE VIRUS

C(3)H/He mice were exposed to total-body X-irradiation of 1000 roentgens and received thereafter 10(7) xenogeneic Wistar rat marrow cells intravenously. In these rat-to-mouse chimeras, serum interferon-producing capacity upon injection of Newcastle disease virus was examined four weeks after grafting. Normal levels of circulating interferon were produced. The interferon, however, had the species specificity of rat interferon, being 20 times more active in rat embryo fibroblasts than in mouse embryo fibroblasts. Moreover, it behaved like rat interferon when filtered on Sephadex G-100 dextran gel, displaying one peak of activity in the 90,000 molecular-weight range and two incompletely separated peaks of 32,000 and 24,000, respectively, in the 30,000 molecular-weight region. The fact that the interferon is of the donor type in rat-to-mouse chimeras permits us to conclude that circulating interferon induced by New-castle disease virus is made in bone-marrow-derived cells

Purification of Mouse Interferon by Affinity Chromatography on a Solid-Phase Immunoadsorbent

A solid-phase immunoadsorbent capable of binding mouse interferon has been prepared. Starting from crude tissue-culture material, interferon could be purified 1990 times in a single step of affinity chromatography. Overall recovery ranged from 55 to 103% with tissue culture and mouse-brain interferon; however, only 5% was obtained with Sendai virus-induced interferon from mouse serum

Interferon-β-Induced Human Immunodeficiency Virus Resistance in CD34+Human Hematopoietic Progenitor Cells: Correlation with a Down-Regulation of CCR-5 Expression

AbstractTo explore the possibility of conferring a long-term resistance against human immunodeficiency virus (HIV) by a low continuous production of interferon-β (IFN-β) in hematopoietic progenitor cells, we transduced the human CD34+TF-1 cells with a retroviral vector ensuring IFN-β production. The IFN-β-transduction of TF-1 cells resulted in resistance to infection with HIV-LAI, as shown by the selective survival of IFN-β-transduced CD4+cells and the protection against HIV-induced apoptosis. A similar response against HIV-LAI infection was obtained after pretreatment with 100 U/ml of recombinant IFN-α2b or IFN-β. In contrast, after the addition of macrophage cell tropic (M cell-tropic) HIV strain, a treatment with exogenous IFN-α2b resulted in a ≧10-fold lower protection compared with exogenous IFN-β or IFN-β transduction. This specific effect of IFN-β on M cell-tropic HIV strains was correlated with a down-regulation of the CCR-5 chemokine receptor expression, corresponding to a novel antiviral effect of IFN-β