Retrovirally Mediated IFN-β Transduction of Macrophages Induces Resistance to HIV, Correlated with Up-Regulation of RANTES Production and Down-Regulation of C-C Chemokine Receptor-5 Expression

Cremer, Isabelle; Vieillard, Vincent; Maeyer, Edward De

doi:10.4049/jimmunol.164.3.1582

Cited by 44 publications

(37 citation statements)

References 47 publications

(35 reference statements)

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“…However, none of the cytokine treatments affected the cell surface expression of CXCR4 or CCR5. This result contrasts with other studies that describe down-regulation of CXCR4 and CCR5 by IFN-␣ in PBMCs or cell lines and macrophages derived from CD34 ϩ cells from umbilical cord blood, respectively (69,70). Conversely, IL-7 up-regulated CXCR4 expression in T cells, PBMCs, and thymocytes, and this effect was associated with increased susceptibility to infection with X4 HIV strains (28,30,32,37).…”

Section: Discussioncontrasting

confidence: 55%

Uncoupled Anti-HIV and Immune-Enhancing Effects when Combining IFN-α and IL-7

Audigé¹,

Schlaepfer²,

Joller

et al. 2005

The Journal of Immunology

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Cytokine-based therapies have been examined for purging viral reservoirs and immunomodulation in HIV infection. However, single cytokines did not result in either HIV eradication or an efficient HIV-specific immune response. We hypothesize that cytokines with distinct biologic effects need to be combined for immunotherapy of HIV infection. In this study, we investigated the anti-HIV activity and immune-enhancing effects of the combination of IFN-α and IL-7. In human lymphocyte aggregate cultures infected ex vivo with the X4 HIV strain NL4-3, IFN-α/IL-7 potently inhibited HIV replication and preserved CD4+ T cells, probably by up-regulating Bcl-2. IFN-α/IL-7 also strongly inhibited R5 HIV replication. Furthermore, in allogeneic MLRs, IFN-α/IL-7 increased T cell proliferation and IFN-γ production. IFN-α alone also had strong anti-HIV activity, but neither preserved CD4+ T cells nor increased T cell responses in MLRs. IL-7 alone maintained T cells and enhanced T cell activation in MLRs, but only moderately inhibited or increased HIV replication. Thus, coadministration of IFN-α/IL-7 combines the potent anti-HIV activity of IFN-α with the beneficial effects of IL-7 on T cell survival and function. We speculate that IFN-α will block viral replication, activate APCs, and up-regulate MHC molecules, thus allowing IL-7 to display its effects for generating an efficient immune response. In this scenario, the known reactivation of latent HIV by IL-7 may be advantageous.

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Section: Discussioncontrasting

confidence: 55%

Uncoupled Anti-HIV and Immune-Enhancing Effects when Combining IFN-α and IL-7

Audigé¹,

Schlaepfer²,

Joller

et al. 2005

The Journal of Immunology

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“…Previous studies focusing on the effects of IFN-␤ have generated conflicting results. High doses of IFN-␤ (1 g/ml) were shown to reduce T cell production of the chemokinetic cytokines RANTES and MIP-1␣ and to reduce lymphocyte chemokinesis (15), but Cremer et al (16,17) found that IFN-␤ induced the production of RANTES in a variety of cell lines. However, the expression of the chemokine receptor CCR5 was down-regulated by IFN-␤, and the net effects of IFN-␤ on T cell migration were not examined.…”

mentioning

confidence: 99%

IFN-α Subtypes Differentially Affect Human T Cell Motility

Foster

Masri

David

et al. 2004

The Journal of Immunology

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The type I IFN family includes 14 closely related antiviral cytokines that are produced in response to viral infections. They bind to a common receptor, and have qualitatively similar biological activities. The physiological relevance of this redundancy is still unclear. In this study, we analyzed and compared the effects of two potent antiviral type I IFNs, IFN-α2 and IFN-α8, on the motility of various populations of human T lymphocytes in vitro. In this study, we show that IFN-α2 induces chemokinesis of both CD4+ and CD8+ T cells at various stages of differentiation, and induces functional changes that result in enhanced T cell motility, including up-regulation of the integrins LFA-1 and VLA-4, and subsequently, increased ICAM-1- and fibronectin-dependent migration. In contrast, IFN-α8 did not affect T cell motility, despite having similar antiviral properties and similar effects on the induction of the antiviral protein MxA. However, transcription of other IFN-stimulated genes showed that transcription of these genes is selectively activated by IFN-α2, but not IFN-α8, in T cells. Finally, while the antiviral activity of the two subtypes is inhibited by Abs against the two subunits of the IFN-α receptor, the chemokinetic effect of IFN-α2 is selectively blocked by Abs against the A1 receptor subunit. These observations are consistent with the possibility that subtype-specific intracellular signaling pathways are activated by type I IFNs in T lymphocytes.

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“…Herpes simplex and adenoviral vectors provide efficient cell transduction of macrophages in vitro, but their use for this purpose in vivo is limited by their immunogenicity. 46 Numerous studies have used retroviral vectors derived from Moloney murine leukemia virus 47 or lentiviruses 48 to transduce CD34+ cells ex vivo. Delivery of anti-HIV ribozyme, dominant negative proteins, or decoys to CD34+ cells partially protected progeny MDMs from HIV replication.…”

Section: Discussionmentioning

confidence: 99%

“…Delivery of anti-HIV ribozyme, dominant negative proteins, or decoys to CD34+ cells partially protected progeny MDMs from HIV replication. 47,[49][50][51][52] Recently, lentivirus vectors used to deliver RNAi against CCR5 were reported to transduce PBMC with low efficiency, and partially protect them from HIV replication. 53 We have found that rSV40 delivery of RNAi may be highly effective in protecting MDMs from R5-tropic HIV.…”

Section: Discussionmentioning

confidence: 99%

Protecting from R5-tropic HIV: individual and combined effectiveness of a hammerhead ribozyme and a single-chain Fv antibody that targets CCR5

Cordelier

Kulkowsky

et al. 2004

Gene Ther

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The CCR5 chemokine receptor is important for most clinical strains of HIV to establish infection. Individuals with naturally occurring polymorphisms in the CCR5 gene who have reduced or absent CCR5 are apparently otherwise healthy, but are resistant to HIV infection. With the goal of reducing CCR5 and protecting CCR5+ cells from R5-tropic HIV, we used Tag-deleted SV40-derived vectors to deliver several anti-CCR5 transgenes: 2C7, a single-chain Fv (SFv) antibody; VCKA1, a hammerhead ribozyme; and two natural CCR5 ligands, MIP-1a and MIP-1b, modified to direct these chemokines, and hence their receptor to the endoplasmic reticulum. These transgenes were delivered using recombinant, Tag-deleted SV40-derived vectors to human CCR5+ cell lines and primary cells: monocyte-derived macrophages and brain microglia. All transgenes except MIP-1a decreased CCR5, as assayed by immunostaining, Northern blotting, and cytofluorimetry (FACS). Individually, all transgenes except MIP-1a protected from low challenge doses of HIV. At higher dose HIV challenges, protection provided by all transgenes diminished, the SFv and the ribozyme being most potent. Vectors carrying these two transgenes were used sequentially to deliver combination anti-CCR5 genetic therapy. This approach gave approximately additive reduction in CCR5, as measured by FACS and protected from higher dose HIV challenges. Reducing cell membrane CCR5 using anti-CCR5 transgenes, alone or in combinations, may therefore provide a degree of protection from R5-tropic strains of HIV.

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Retrovirally Mediated IFN-β Transduction of Macrophages Induces Resistance to HIV, Correlated with Up-Regulation of RANTES Production and Down-Regulation of C-C Chemokine Receptor-5 Expression

Cited by 44 publications

References 47 publications

Uncoupled Anti-HIV and Immune-Enhancing Effects when Combining IFN-α and IL-7

Uncoupled Anti-HIV and Immune-Enhancing Effects when Combining IFN-α and IL-7

IFN-α Subtypes Differentially Affect Human T Cell Motility

Protecting from R5-tropic HIV: individual and combined effectiveness of a hammerhead ribozyme and a single-chain Fv antibody that targets CCR5

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