scholarly journals Interference with SAMHD1 Restores Late Gene Expression of Modified Vaccinia Virus Ankara in Human Dendritic Cells and Abrogates Type I Interferon Expression

2019 ◽  
Vol 93 (22) ◽  
Author(s):  
Katja Sliva ◽  
Judith Martin ◽  
Christine von Rhein ◽  
Tobias Herrmann ◽  
Anastasia Weyrich ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Dna Replication ◽  
Vaccinia Virus ◽  
Type I Interferon ◽  
Type I ◽  
Late Gene Expression ◽  
Host Interactions ◽  
Modified Vaccinia Virus Ankara ◽  
Immunodeficiency Virus ◽  
Human Dendritic Cells

ABSTRACT Attenuated poxviruses like modified vaccinia virus Ankara (MVA) are promising vectors for vaccines against infectious diseases and cancer. However, host innate immune responses interfere with the viral life cycle and also influence the immunogenicity of vaccine vectors. Sterile alpha motif (SAM) domain and histidine-aspartate (HD) domain-containing protein 1 (SAMHD1) is a phosphohydrolase and reduces cellular deoxynucleoside triphosphate (dNTP) concentrations, which impairs poxviral DNA replication in human dendritic cells (DCs). Human immunodeficiency virus type 2 (HIV-2) and simian immunodeficiency virus (SIV) encode an accessory protein called viral protein X (Vpx) that promotes proteasomal degradation of SAMHD1, leading to a rapid increase in cellular dNTP concentrations. To study the function of SAMHD1 during MVA infection of human DCs, the SIV vpx gene was introduced into the MVA genome (resulting in recombinant MVA-vpx). Infection of human DCs with MVA-vpx led to SAMHD1 protein degradation and enabled MVA-vpx to replicate its DNA genome and to express genes controlled by late promoters. Late gene expression by MVA-vpx might improve its vaccine vector properties; however, type I interferon expression was unexpectedly blocked by Vpx-expressing MVA. MVA-vpx can be used as a tool to study poxvirus-host interactions and vector safety. IMPORTANCE SAMHD1 is a phosphohydrolase and reduces cellular dNTP concentrations, which impairs poxviral DNA replication. The simian SIV accessory protein Vpx promotes degradation of SAMHD1, leading to increased cellular dNTP concentrations. Vpx addition enables poxviral DNA replication in human dendritic cells (DCs), as well as the expression of viral late proteins, which is normally blocked. SAMHD1 function during modified vaccinia virus Ankara (MVA) infection of human DCs was studied with recombinant MVA-vpx expressing Vpx. Infection of human DCs with MVA-vpx decreased SAMHD1 protein amounts, enabling MVA DNA replication and expression of late viral genes. Unexpectedly, type I interferon expression was blocked after MVA-vpx infection. MVA-vpx might be a good tool to study SAMHD1 depletion during poxviral infections and to provide insights into poxvirus-host interactions.

scholarly journals Regulatory NLRs Control the RLR-Mediated Type I Interferon and Inflammatory Responses in Human Dendritic Cells

2018 ◽  
Vol 9 ◽  
Author(s):  
Tünde Fekete ◽  
Dora Bencze ◽  
Attila Szabo ◽  
Eszter Csoma ◽  
Tamas Biro ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Inflammatory Responses ◽  
Type I Interferon ◽  
Type I ◽  
Human Dendritic Cells

scholarly journals Dengue Virus Inhibits the Production of Type I Interferon in Primary Human Dendritic Cells

2011 ◽  
Vol 85 (6) ◽  
pp. 3042-3042
Author(s):  
J. R. Rodriguez-Madoz ◽  
D. Bernal-Rubio ◽  
D. Kaminski ◽  
K. Boyd ◽  
A. Fernandez-Sesma
Keyword(s):  
Dendritic Cells ◽  
Dengue Virus ◽  
Type I Interferon ◽  
Type I ◽  
Human Dendritic Cells

scholarly journals Modified Vaccinia Virus Ankara Triggers Type I IFN Production in Murine Conventional Dendritic Cells via a cGAS/STING-Mediated Cytosolic DNA-Sensing Pathway

2014 ◽  
Vol 10 (4) ◽  
pp. e1003989 ◽  
Author(s):  
Peihong Dai ◽  
Weiyi Wang ◽  
Hua Cao ◽  
Francesca Avogadri ◽  
Lianpan Dai ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Vaccinia Virus ◽  
Type I ◽  
Type I Ifn ◽  
Dna Sensing ◽  
Modified Vaccinia Virus Ankara

scholarly journals Modulation of Type I Interferon-Associated Viral Sensing during Acute Simian Immunodeficiency Virus Infection in African Green Monkeys

2014 ◽  
Vol 89 (1) ◽  
pp. 751-762 ◽  
Author(s):  
Simon P. Jochems ◽  
Gaël Petitjean ◽  
Désirée Kunkel ◽  
Anne-Sophie Liovat ◽  
Mickaël J. Ploquin ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Simian Immunodeficiency Virus ◽  
Blood Cells ◽  
Type I Interferon ◽  
Acute Infection ◽  
Plasmacytoid Dendritic Cells ◽  
Type I ◽  
Immunodeficiency Virus ◽  
Siv Infection ◽  
Green Monkeys

ABSTRACTNatural hosts of simian immunodeficiency virus (SIV), such as African green monkeys (AGMs), do not progress to AIDS when infected with SIV. This is associated with an absence of a chronic type I interferon (IFN-I) signature. It is unclear how the IFN-I response is downmodulated in AGMs. We longitudinally assessed the capacity of AGM blood cells to produce IFN-I in response to SIV and herpes simplex virus (HSV) infection. Phenotypes and functions of plasmacytoid dendritic cells (pDCs) and other mononuclear blood cells were assessed by flow cytometry, and expression of viral sensors was measured by reverse transcription-PCR. pDCs displayed low BDCA-2, CD40, and HLA-DR expression levels during AGM acute SIV (SIVagm) infection. BDCA-2 was required for sensing of SIV, but not of HSV, by pDCs. In acute infection, AGM peripheral blood mononuclear cells (PBMCs) produced less IFN-I upon SIV stimulation. In the chronic phase, the production was normal, confirming that the lack of chronic inflammation is not due to a sensing defect of pDCs. In contrast to stimulation by SIV, more IFN-I was produced upon HSV stimulation of PBMCs isolated during acute infection, while the frequency of AGM pDCs producing IFN-I uponin vitrostimulation with HSV was diminished. Indeed, other cells started producing IFN-I. This increased viral sensing by non-pDCs was associated with an upregulation of Toll-like receptor 3 and IFN-γ-inducible protein 16 caused by IFN-I in acute SIVagm infection. Our results suggest that, as in pathogenic SIVmac infection, SIVagm infection mobilizes bone marrow precursor pDCs. Moreover, we show that SIV infection modifies the capacity of viral sensing in cells other than pDCs, which could drive IFN-I production in specific settings.IMPORTANCEThe effects of HIV/SIV infections on the capacity of plasmacytoid dendritic cells (pDCs) to produce IFN-Iin vivoare still incompletely defined. As IFN-I can restrict viral replication, contribute to inflammation, and influence immune responses, alteration of this capacity could impact the viral reservoir size. We observed that even in nonpathogenic SIV infection, the frequency of pDCs capable of efficiently sensing SIV and producing IFN-I was reduced during acute infection. We discovered that, concomitantly, cells other than pDCs had increased abilities for viral sensing. Our results suggest that pDC-produced IFN-I upregulates viral sensors in bystander cells, the latter gaining the capacity to produce IFN-I. These results indicate that in certain settings, cells other than pDCs can drive IFN-I-associated inflammation in SIV infection. This has important implications for the understanding of persistent inflammation and the establishment of viral reservoirs.

scholarly journals Selective blockade of the inhibitory Fcγ receptor (FcγRIIB) in human dendritic cells and monocytes induces a type I interferon response program

2007 ◽  
Vol 204 (10) ◽  
pp. 2489-2489 ◽  
Author(s):  
Kavita M. Dhodapkar ◽  
Devi Banerjee ◽  
John Connolly ◽  
Anjli Kukreja ◽  
Elyana Matayeva ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Type I Interferon ◽  
Interferon Response ◽  
Type I ◽  
Fcγ Receptor ◽  
Selective Blockade ◽  
Human Dendritic Cells

scholarly journals Vaccinia Virus-Mediated Inhibition of Type I Interferon Responses Is a Multifactorial Process Involving the Soluble Type I Interferon Receptor B18 and Intracellular Components

2008 ◽  
Vol 83 (4) ◽  
pp. 1563-1571 ◽  
Author(s):  
Zoe Waibler ◽  
Martina Anzaghe ◽  
Theresa Frenz ◽  
Astrid Schwantes ◽  
Christopher Pöhlmann ◽  
...  
Keyword(s):  
Vaccinia Virus ◽  
Type I Interferon ◽  
Poly I:C ◽  
Host Responses ◽  
Type I ◽  
Immune Modulators ◽  
Modified Vaccinia Virus Ankara ◽  
Multistep Process ◽  
Interferon Responses

ABSTRACT Poxviruses such as virulent vaccinia virus (VACV) strain Western Reserve encode a broad range of immune modulators that interfere with host responses to infection. Upon more than 570 in vitro passages in chicken embryo fibroblasts (CEF), chorioallantois VACV Ankara (CVA) accumulated mutations that resulted in highly attenuated modified vaccinia virus Ankara (MVA). MVA infection of mice and of dendritic cells (DC) induced significant type I interferon (IFN) responses, whereas infection with VACV alone or in combination with MVA did not. These results implied that VACV expressed an IFN inhibitor(s) that was functionally deleted in MVA. To further characterize the IFN inhibitor(s), infection experiments were carried out with CVA strains isolated after 152 (CVA152) and 386 CEF passages (CVA386). Interestingly, neither CVA152 nor CVA386 induced IFN-α, whereas the latter variant did induce IFN-β. This pattern suggested a consecutive loss of inhibitors during MVA attenuation. Similar to supernatants of VACV- and CVA152-infected DC cultures, recombinantly expressed soluble IFN decoy receptor B18, which is encoded in the VACV genome, inhibited MVA-induced IFN-α but not IFN-β. In the same direction, a B18R-deficient VACV variant triggered only IFN-α, confirming B18 as the soluble IFN-α inhibitor. Interestingly, VACV infection inhibited IFN responses induced by a multitude of different stimuli, including oligodeoxynucleotides containing CpG motifs, poly(I:C), and vesicular stomatitis virus. Collectively, the data presented show that VACV-mediated IFN inhibition is a multistep process involving secreted factors such as B18 plus intracellular components that cooperate to efficiently shut off systemic IFN-α and IFN-β responses.

scholarly journals Differences and Similarities in Viral Life Cycle Progression and Host Cell Physiology after Infection of Human Dendritic Cells with Modified Vaccinia Virus Ankara and Vaccinia Virus

2006 ◽  
Vol 80 (17) ◽  
pp. 8469-8481 ◽  
Author(s):  
Ann Chahroudi ◽  
David A. Garber ◽  
Patrick Reeves ◽  
Luzheng Liu ◽  
Daniel Kalman ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Immune Responses ◽  
Vaccinia Virus ◽  
Viral Vector ◽  
Cellular Protein ◽  
Distinct Pattern ◽  
Cell Physiology ◽  
Human Immune System ◽  
Modified Vaccinia Virus Ankara ◽  
Human Dendritic Cells

ABSTRACT Modified vaccinia virus Ankara (MVA) is an attenuated strain of vaccinia virus (VV) that has attracted significant attention as a candidate viral vector vaccine for immunization against infectious diseases and treatment of malignancies. Although MVA is unable to replicate in most nonavian cells, vaccination with MVA elicits immune responses that approximate those seen after the administration of replication-competent strains of VV. However, the mechanisms by which these viruses elicit immune responses and the determinants of their relative immunogenicity are incompletely understood. Studying the interactions of VV and MVA with cells of the human immune system may elucidate these mechanisms, as well as provide a rational basis for the further enhancement of the immunogenicity of recombinant MVA vectors. Toward this end, we investigated the consequences of MVA or VV infection of human dendritic cells (DCs), key professional antigen-presenting cells essential for the generation of immune responses. We determined that a block to the formation of intracellular viral replication centers results in abortive infection of DCs with both VV and MVA. MVA inhibited cellular protein synthesis more rapidly than VV and displayed a distinct pattern of viral protein expression in infected DCs. MVA also induced apoptosis in DCs more rapidly than VV, and DC apoptosis after MVA infection was associated with an accelerated decline in the levels of intracellular Bcl-2 and Bcl-XL. These findings suggest that antigen presentation pathways may contribute differentially to the immunogenicity of VV and MVA and that targeted modifications of virus-induced DC apoptosis may further increase the immunogenicity of MVA-vectored vaccines.

scholarly journals Zika Virus Antagonizes Type I Interferon Responses during Infection of Human Dendritic Cells

2017 ◽  
Vol 13 (2) ◽  
pp. e1006164 ◽  
Author(s):  
James R. Bowen ◽  
Kendra M. Quicke ◽  
Mohan S. Maddur ◽  
Justin T. O’Neal ◽  
Circe E. McDonald ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Zika Virus ◽  
Type I Interferon ◽  
Type I ◽  
Human Dendritic Cells ◽  
Interferon Responses
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