The IFITMs Inhibit Zika Virus Replication

Savidis, George; Perreira, Jill M.; Portmann, Jocelyn M.; Meraner, Paul; Guo, Zhiru; Green, Sharone; Brass, Abraham L.

doi:10.1016/j.celrep.2016.05.074

Cited by 207 publications

(214 citation statements)

References 31 publications

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“…Further evidence comes from recent studies showing that the host controls ZIKV infection through IFN signaling pathways (Bayer et al, 2016), which protect cells from viral infection by inducing numerous ISGs (Sadler and Williams, 2008). Recently, interferon-induced transmembrane 1 and 3 proteins (IFITM1 and IFITM3) were demonstrated to inhibit ZIKV infection in early stages of the viral life cycle, and IFITM3 can prevent ZIKV-induced cell death (Savidis et al, 2016). However, the role of other ISGs in host immunity against ZIKV infection remains largely elusive.…”

Section: Introductionmentioning

confidence: 99%

25-Hydroxycholesterol Protects Host against Zika Virus Infection and Its Associated Microcephaly in a Mouse Model

et al. 2017

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SUMMARY Zika virus (ZIKV) has become a public health threat due to its global transmission and link to severe congenital disorders. The host immune responses to ZIKV infection have not been fully elucidated, and effective therapeutics are not currently available. Herein, we demonstrated that cholesterol-25-hydroxylase (CH25H) was induced in response to ZIKV infection and that its enzymatic product, 25-hydroxycholesterol (25HC), was a critical mediator of host protection against ZIKV. Synthetic 25HC addition inhibited ZIKV infection in vitro by blocking viral entry, and treatment with 25HC reduced viremia and conferred protection against ZIKV in mice and rhesus macaques. 25HC suppressed ZIKV infection and reduced tissue damage in human cortical organoids and the embryonic brain of the ZIKV-induced mouse microcephaly model. Our findings highlight the protective role of CH25H during ZIKV infection and the potential use of 25HC as a natural antiviral agent to combat ZIKV infection and prevent ZIKV-associated outcomes, such as microcephaly.

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Section: Introductionmentioning

confidence: 99%

25-Hydroxycholesterol Protects Host against Zika Virus Infection and Its Associated Microcephaly in a Mouse Model

et al. 2017

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“…Specifically, the IFN-induced transmembrane proteins, IFITM2 and IFITM3, have been shown to restrict infection at early stages of the viral life cycle and provide protection against ZIKV-induced cytopathic effects in HeLa cells [10]. Additionally, viperin, another antiviral ISG, is able to restrict replication in human hepatoma cells; and viperin knockout mouse embryonic fibroblast cells produce higher ZIKV titers than wild-type cells [11].…”

Section: Type I Ifn Stimulated Genes Restrict Zikv Infectionmentioning

confidence: 99%

“…Recent investigations have demonstrated that several ISGs are able to restrict ZIKV infection [10]. Specifically, the IFN-induced transmembrane proteins, IFITM2 and IFITM3, have been shown to restrict infection at early stages of the viral life cycle and provide protection against ZIKV-induced cytopathic effects in HeLa cells [10].…”

Section: Type I Ifn Stimulated Genes Restrict Zikv Infectionmentioning

confidence: 99%

“…This signaling cascade leads to the transcription of more than 300 ISGs, creating a cellular environment resistant to viral replication. It is well established that type I IFN induction is able to restrict ZIKV infection in cell culture [5][6][7][8] and in mouse models [6,9].Recent investigations have demonstrated that several ISGs are able to restrict ZIKV infection [10]. Specifically, the IFN-induced transmembrane proteins, IFITM2 and IFITM3, have been shown to restrict infection at early stages of the viral life cycle and provide protection against ZIKV-induced cytopathic effects in HeLa cells [10].…”

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confidence: 99%

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Zika Virus Infection: Induction, Restriction and Evasion of Host Interferon Responses

2017

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Zika virus (ZIKV) is an arthropod-borne flavivirus that has become a significant global health concern due to its rapid geographic expansion and association with novel neurological pathogenesis [1]. The recent emergence of ZIKV is multifactorial and likely includes the expanded geographical range of Aedes sp. mosquitoes, the immunological naivety of human populations outside of historically endemic regions and global travel of infected individuals [2]. In addition to these epidemiological consequences of globalization, ZIKV has evolved novel mechanisms to induce disease pathogenesis and evade host immune responses [1,2]. Understanding how recently acquired viral polymorphisms influence viral pathogenesis and the host immune response during infection is crucial to further our understanding of ZIKV infection and pathogenesis.ZIKV is a single-stranded, positive-sense RNA virus that encodes a single polyprotein that is catalytically processed by host and viral proteases into three structural proteins (C, prM and E) and seven nonstructural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B and NS5). The structural proteins form the virion particle are the primary targets for the host humoral immune response [1,2]. The multifunctional nonstructural proteins have been implicated in polyprotein processing, viral RNA replication, virion assembly, as well as evasion of the innate immune response [1]. Herein, we review recent findings regarding how the interferon (IFN) response restricts ZIKV infection and the ways in which ZIKV is able to overcome IFN signaling to circumvent innate immunity. Type I IFN stimulated genes restrict ZIKV infectionType I IFNs (IFNα/β) are transcriptionally regulated and induced following recognition of pathogen components during infection by various host pattern recognition receptors. Activation of pattern recognition receptors leads to synthesis of type I IFNs that trigger antiviral responses by binding to a common type I IFN receptor. Receptor binding stimulates the JAK kinases, which phosphorylate STAT1 and STAT2, leading to the assembly of the ISGF3 complex, composed of STAT1-STAT2 dimers and IRF9, which translocates to the nucleus and binds to IFN-stimulated response elements in the promoters of interferon stimulated genes (ISGs) to regulate their expression [3,4]. This signaling cascade leads to the transcription of more than 300 ISGs, creating a cellular environment resistant to viral replication. It is well established that type I IFN induction is able to restrict ZIKV infection in cell culture [5][6][7][8] and in mouse models [6,9].Recent investigations have demonstrated that several ISGs are able to restrict ZIKV infection [10]. Specifically, the IFN-induced transmembrane proteins, IFITM2 and IFITM3, have been shown to restrict infection at early stages of the viral life cycle and provide protection against ZIKV-induced cytopathic effects in HeLa cells [10]. Additionally, viperin, another antiviral ISG, is able to restrict replication in human hepatoma cells; and viperin knockout mouse embryo...

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“…Although the functions of many activated genes are not clear, several can inhibit both viral infection and replication. A class of interesting molecules includes the interferon-induced transmembrane (IFITM) proteins that have been reported to inhibit infection by a broad spectrum of viruses (44)(45)(46)(47)(48)(49)(50). This may result from a decrease of viral transmission into cells, involving decreased fusion between viral envelopes and cellular membranes.…”

Section: Figmentioning

confidence: 99%

JAK-STAT Signaling Pathways and Inhibitors Affect Reversion of Envelope-Mutated HIV-1

Quan

Han

et al. 2017

J Virol

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HIV can spread by both cell-free and cell-to-cell transmission. Here, we show that many of the amino acid changes in Env that are close to the CD4 binding pocket can affect HIV replication. We generated a number of mutant viruses that were unable to infect T cells as cell-free viruses but were nevertheless able to infect certain T cell lines as cell-associated viruses, which was followed by reversion to the wild type. However, the activation of JAK-STAT signaling pathways caused the inhibition of such cell-to-cell infection as well as the reversion of multiple HIV Env mutants that displayed differences in their abilities to bind to the CD4 receptor. Specifically, two T cell activators, interleukin-2 (IL-2) and phorbol 12-myristate 13-acetate (PMA), both capable of activation of JAK-STAT pathways, were able to inhibit cell-tocell viral transmission. In contrast, but consistent with the above result, a number of JAK-STAT and mTOR inhibitors actually promoted HIV-1 transmission and reversion. Hence, JAK-STAT signaling pathways may differentially affect the replication of a variety of HIV Env mutants in ways that differ from the role that these pathways play in the replication of wild-type viruses.IMPORTANCE Specific alterations in HIV Env close to the CD4 binding site can differentially change the ability of HIV to mediate infection for cell-free and cell-associated viruses. However, such differences are dependent to some extent on the types of target cells used. JAK-STAT signaling pathways are able to play major roles in these processes. This work sheds new light on factors that can govern HIV infection of target cells.KEYWORDS HIV-1, Env mutant, cell-associated viruses, cell dependence, reversion H IV-1 infection of cells can be efficiently established by free virus or directly via cell-cell contact, both involving the binding of the HIV gp120 protein to the cellular CD4 receptor and either the CCR5 or CXCR4 coreceptor (1-3). It has been reported that cell-to-cell transmission is more physiologically relevant and efficient although cell-free HIV may be used to initiate new infections in tissue culture (4-7).HIV-1 entry into target cells is believed to be a multistep and complex process initiated by the envelope protein gp120 binding to cell surface CD4, triggering conformational changes of gp120, followed by a second-step interaction between gp120 and either CXCR4 or CCR5, resulting in fusion between the viral envelope and the cellular plasma membrane (8). In addition to viral gp120 and other viral proteins, several host cell components, including intrinsic immune factors (9) and histocompatibility antigens, can influence HIV infectivity (10, 11). However, some viral factors can also counteract innate host defense mechanisms (12). It has also been reported that HIV can under some circumstances enter target cells via a CD4/coreceptor-independent mechanism (13-18), potentially broadening the spectrum of cells that HIV is able to infect.

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The IFITMs Inhibit Zika Virus Replication

Cited by 207 publications

References 31 publications

25-Hydroxycholesterol Protects Host against Zika Virus Infection and Its Associated Microcephaly in a Mouse Model

25-Hydroxycholesterol Protects Host against Zika Virus Infection and Its Associated Microcephaly in a Mouse Model

Zika Virus Infection: Induction, Restriction and Evasion of Host Interferon Responses

JAK-STAT Signaling Pathways and Inhibitors Affect Reversion of Envelope-Mutated HIV-1

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