Innate Sensing of Foamy Viruses by Human Hematopoietic Cells

Rua, Réjane; Lepelley, Alice; Gessain, Antoine; Schwartz, Olivier

doi:10.1128/jvi.06235-11

Cited by 30 publications

(36 citation statements)

References 81 publications

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“…Thus, in this context, IFI35 exhibits an antiviral role and suppresses virus replication. Since infection of HeLa or HEK293 cells (which are of a nonhematopoietic origin) by foamy viruses does not induce a type I IFN response (50,51), it is possible that the negative regulatory role of IFI35 in innate immune signaling was not observed readily in these studies. However, our data clearly demonstrate the supportive role of IFI35 in VSV infection through negative regulation of innate immune signaling.…”

Section: Discussionmentioning

confidence: 95%

Interferon-Inducible Protein IFI35 Negatively Regulates RIG-I Antiviral Signaling and Supports Vesicular Stomatitis Virus Replication

Das

Dinh

Panda

et al. 2014

J Virol

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In a genome-wide small interfering RNA (siRNA) screen, we recently identified the interferon (IFN)-inducible protein 35 (IFI35; also known as IFP35) as a factor required for vesicular stomatitis virus (VSV) infection. Studies reported here were conducted to further understand the role and requirement of IFI35 in VSV infection. Consistent with the siRNA screening data, we found that depletion of IFI35 led to reduced VSV replication at the level of viral gene expression. Although no direct interaction of IFI35 with the viral replication machinery was observed, we found that IFI35 negatively regulated the host innate immune response and rescued poly(I·C)-induced inhibition of VSV replication. Promoter-driven reporter gene assays demonstrated that IFI35 overexpression suppressed the activation of IFN-␤ and ISG56 promoters, whereas its depletion had the opposite effect. Further investigation revealed that IFI35 specifically interacted with retinoic acid-inducible gene I (RIG-I) and negatively regulated its activation through mechanisms that included (i) suppression of dephosphorylation (activation) of RIG-I and (ii) proteasome-mediated degradation of RIG-I via K48-linked ubiquitination. Overall, the results presented here suggest a novel role for IFI35 in negative regulation of RIG-I-mediated antiviral signaling, which will have implications for diseases associated with excessive immune signaling. IMPORTANCE Mammalian cells employ a variety of mechanisms, including production of interferons (IFNs), to counteract invading pathogens. In this study, we identified a novel role for a cellular protein, IFN-inducible protein 35 (IFP35/IFI35), in negatively regulating the host IFN response during vesicular stomatitis virus (VSV) infection. Specifically, we found that IFI35 inhibited activation of the RNA sensor, the retinoic acid-inducible gene I (RIG-I), leading to inhibition of IFN production and thus resulting in better replication of VSV. The identification of a cellular factor that attenuates the IFN response will have implications toward understanding inflammatory diseases in humans that have been found to be associated with defects in the regulation of host IFN production, such as systemic lupus erythematosus and psoriasis.

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Section: Discussionmentioning

confidence: 95%

Interferon-Inducible Protein IFI35 Negatively Regulates RIG-I Antiviral Signaling and Supports Vesicular Stomatitis Virus Replication

Das

Dinh

Panda

et al. 2014

J Virol

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“…A failure of FVs to induce type I interferon (IFN-I) was suggested by early studies using primate or human cell lines [73,74,75]. A very recent study by Rua and colleagues, however, demonstrates that FVs are efficiently sensed by primary human hematopoietic cells [76]. Plasmacytoid dendritic cells (pDC), the main IFN-producing cell in the organism, appeared to be the major source of IFN-I production in human peripheral blood mononuclear cells (PBMC) stimulated with FV particles or FV infected cells.…”

Section: Innate Sensing and Cellular Restriction Factors Of Fvsmentioning

confidence: 99%

Early Events in Foamy Virus—Host Interaction and Intracellular Trafficking

Berka

Hamann

Lindemann

2013

Viruses

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Here we review viral and cellular requirements for entry and intracellular trafficking of foamy viruses (FVs) resulting in integration of viral sequences into the host cell genome. The virus encoded glycoprotein harbors all essential viral determinants, which are involved in absorption to the host membrane and triggering the uptake of virus particles. However, only recently light was shed on some details of FV’s interaction with its host cell receptor(s). Latest studies indicate glycosaminoglycans of cellular proteoglycans, particularly heparan sulfate, to be of utmost importance. In a species-specific manner FVs encounter endogenous machineries of the target cell, which are in some cases exploited for fusion and further egress into the cytosol. Mostly triggered by pH-dependent endocytosis, viral and cellular membranes fuse and release naked FV capsids into the cytoplasm. Intact FV capsids are then shuttled along microtubules and are found to accumulate nearby the centrosome where they can remain in a latent state for extended time periods. Depending on the host cell cycle status, FV capsids finally disassemble and, by still poorly characterized mechanisms, the preintegration complex gets access to the host cell chromatin. Host cell mitosis finally allows for viral genome integration, ultimately starting a new round of viral replication.

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“…TLR7 is expressed in cells of several immune lineages, including B cells, dendritic cells (DCs), and macrophages, and TLR7 ligation in vitro triggers numerous changes in gene expression, including expression of several cytokines (10). Importantly, TLR7 has been identified as a sensing pathway for several members of the retrovirus family, including HIV-1, foamy viruses, and murine gammaretroviruses (11)(12)(13)(14)(15). In vitro studies have shown that retroviral particles stimulate secretion of some cytokines from myeloid and plasmacytoid dendritic cells in a TLR7-dependent manner (11,16).…”

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confidence: 99%

Toll-Like Receptor 7 Inhibits Early Acute Retroviral Infection through Rapid Lymphocyte Responses

Browne

2013

J Virol

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Early events during retroviral infection play a critical role in determining the course of infection and pathogenesis, but the mechanisms that regulate this phase of infection are poorly understood. Toll-like receptor 7 (TLR7) is required for promoting germinal center reactions and virus-specific neutralizing antibodies at later time points postinfection, but TLR7's role in early acute infection has not been determined. By infecting TLR7-deficient mice with a retroviral pathogen, Friend virus (FV), I determined that TLR7 potently inhibits retroviral replication during the first 5 days of infection and is required for rapid secretion of virus-specific IgM and interleukin-10 (IL-10) in response to infection. Although the IgM response was nonneutralizing, plasmas from wild-type mice but not TLR7-deficient mice inhibited FV replication when passively transferred to infected mice, suggesting an indirect mechanism of antibody function. Interestingly, IL-10 was secreted primarily by CD4 T cells, and IL-10-deficient mice also exhibited accelerated early virus spread, demonstrating that this response inhibits acute infection. Surprisingly, TLR7-deficient mice exhibited normal or elevated secretion of proinflammatory cytokines during acute infection, revealing the existence of a TLR7-independent retrovirus-sensing pathway that drives inflammatory cytokine secretion. Together, these results establish a previously unappreciated role for lymphocytes in mediating rapid TLR7-dependent inhibition of early retroviral infection through nonneutralizing IgM and IL-10.

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Innate Sensing of Foamy Viruses by Human Hematopoietic Cells

Cited by 30 publications

References 81 publications

Interferon-Inducible Protein IFI35 Negatively Regulates RIG-I Antiviral Signaling and Supports Vesicular Stomatitis Virus Replication

Interferon-Inducible Protein IFI35 Negatively Regulates RIG-I Antiviral Signaling and Supports Vesicular Stomatitis Virus Replication

Early Events in Foamy Virus—Host Interaction and Intracellular Trafficking

Toll-Like Receptor 7 Inhibits Early Acute Retroviral Infection through Rapid Lymphocyte Responses

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