Alpha Interferon Restricts Human T-Lymphotropic Virus Type 1 and 2
            <i>De Novo</i>
            Infection through PKR Activation

Cachat, Anne; Chevalier, Sébastien Alain; Alais, Sandrine; Ko, Nga Ling; Ratner, Lee; Journo, Chloé; Dutartre, Hélène; Mahieux, Renaud

doi:10.1128/jvi.02758-13

Cited by 28 publications

(42 citation statements)

References 70 publications

(63 reference statements)

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“…Surprisingly, neither treatment of immature DCs with recombinant IFN-α nor culture with supernatant from mature DCs (that contains high amounts of physiological type I IFNs) was able to restrict HTLV-1 infection. This is in contrast with previous studies [19,20] and suggests that therapeutic failure of type I IFN therapy used in some ATL chemotherapy protocols [21] could be due to resistance of DCs to IFN-α treatment. This hypothesis would need confirmation through clinical trials monitoring the proviral load in DCs from ATL patients throughout anti-viral therapy.…”

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confidence: 54%

“…This led to the observation that the strength of HTLV-1 restriction correlates the level of DC maturation. Because mature DCs produce high amounts of IFN-α and because it is well established that IFN-α has anti-HTLV-1 activity in other cell types [19,20], we then asked whether HTLV-1 restriction in mature DCs was due to the antiviral effect of IFN-α. Surprisingly, neither treatment of immature DCs with recombinant IFN-α nor culture with supernatant from mature DCs (that contains high amounts of physiological type I IFNs) was able to restrict HTLV-1 infection.…”

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confidence: 99%

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How Does Susceptibility to HTLV-1 Infection Varies With the Maturation State of Dendritic Cells?

et al. 2017

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Keywords: dendritic cells • dendritic cell maturation • HTLV-1 infection • viral infectionHuman T-lymphotropic virus type 1 (HTLV-1) is the etiological agent of adult T-cell leukemia/lymphoma and HTLV-1-associated myelopathy. In patients, the provirus is detected in CD4 + T cells. HTLV-1 also infects blood or monocyte-derived dendritic cells (DCs) in vitro. Since DCs are more susceptible to HTLV-1 infection than autologous T cells, it has been suggested that they might be intermediaries for the viral spread to lymphocytes. DCs can switch from an immature to a mature state after contact with pathogens. In other viral infection, mature DCs are more efficient than immature DCs in viral transmission to T cells. In this editorial, we highlight a work demonstrating that mature DCs are unable to transmit HTLV-1 to T cells and discuss the mechanism of such restriction.HTLV-1 was identified as the first human oncogenic retrovirus [1,2]. It is the etiological agent of adult T-cell leukemia (ATL), an oligoclonal malignancy of infected CD4 + T lymphocytes, and of tropical spastic paraparesis, a chronic progressive inflammatory disease. Five to ten million individuals are HTLV-1 carriers worldwide [3], a probably underestimated number. HTLV-1 inter-individual transmission relies on mother-to-child transmission through prolonged breastfeeding, on sexual transmission and on transmission with contaminated blood products [4].In chronically infected individuals, HTLV-1 proviral DNA is mainly found in CD4 + T cells, but several reports have demonstrated that others immune cell types are infected by HTLV-1 in vivo [5][6][7]. These cell types include DCs, which are specialized antigen-presenting cells and essential mediators in shaping innate and adaptive immunity [8]. In vitro studies conducted by our lab and others confirmed that HTLV-1 productively infects myeloid blood DCs [7] and monocyte-derived DCs (MDDCs) [9][10][11]. Of note, exposure of target cells to cell-free viruses only leads to very low levels of productive infection [9], consistent with the observation that efficient infection of target cells requires close cell-to-cell contacts with infected donor cells [12]. Viral entry in T cells requires expression of the HTLV-1 receptor complex, in other words, neuropilin-1 and heparan sulfate proteoglycans, used for binding [13], and the glucose transporter Glut-1, required for fusion [14], while viral binding to DCs was also shown to require DC-SIGN [11].Importantly, we demonstrated that primary MDDCs are more susceptible to productive HTLV-1 infection than their autologous T cells [9]. Given that productively infected MDDCs are able to transfer HTLV-1 to T cells [7,9,11], it is thus proposed that DCs might be important intermediaries for HTLV-1 spread to T cells in newly infected individuals.Upon stimulation, DCs can switch from an immature to a mature state characterized by morphological, phenotypic and functional changes [15]. Interestingly, in the context of HIV-1, another retrovirus that spreads from DCs to T cells in ne...

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How Does Susceptibility to HTLV-1 Infection Varies With the Maturation State of Dendritic Cells?

et al. 2017

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“…1A). We have previously shown that passive Tax protein transfer from donor to target cells does not occur in this setting (20). Thus, luciferase activity represents a readout of productive infection.…”

Section: C91pl Cells Produce More Infectious Viral Particles Than Mt-mentioning

confidence: 99%

“…Several HTLV-1 chronically infected T-cell lines are available for in vitro studies and have been used to infect T lymphocytes (17,20,21). However, DC infection was performed using MT-2 cells only (10,22), while HTLV-1 transcytosis experiments were done using C91PL cells only (19).…”

Section: C91pl Cells Produce More Infectious Viral Particles Than Mt-mentioning

confidence: 99%

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Viral Source-Independent High Susceptibility of Dendritic Cells to Human T-Cell Leukemia Virus Type 1 Infection Compared to That of T Lymphocytes

Alais

Mahieux

Dutartre

2015

J Virol

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109

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Human T-cell leukemia virus type 1 (HTLV-1)-infected CD4؉ T cells and dendritic cells (DCs) are present in peripheral blood from HTLV-1 carriers. While T-cell infection requires cell-cell contact, DCs might be infected with cell-free virus, at least in vitro. However, a thorough comparison of the susceptibilities of the two cell types to HTLV-1 infection using cell-associated and cell-free viral sources has not been performed. We first determined that human primary monocyte-derived dendritic cells (MDDCs) were more susceptible to HTLV-1 infection than their autologous lymphocyte counterparts after contact with chronically infected cells. Next, a comparison of infection efficiency using nonconcentrated or concentrated supernatants from infected cells as well as purified viral biofilm was performed. Integrated provirus was found after exposure of MDDCs or primary lymphocytes to viral biofilm but not to a viral supernatant. Using a large series of primary cell samples (n ‫؍‬ 21), we demonstrated a higher proviral load in MDDCs exposed to viral biofilm than in lymphocytes. This higher susceptibility is correlated to a higher expression of neuropilin-1 on MDDCs than on autologous activated T lymphocytes. Moreover, we show that MDDCs infected with viral biofilm can transmit the virus to lymphocytes. In conclusion, MDDCs are more susceptible to HTLV-1 infection than autologous lymphocytes in vitro, supporting a model in which DC infection might represent an important step during primoinfection in vivo. IMPORTANCEHTLV-1 is able to infect several cell types, but viral DNA is mainly found in T lymphocytes in vivo. This supports a model in which T lymphocytes are the main target of infection. However, during the primo-infection of new individuals, incoming viruses might first encounter dendritic cells (DCs), the specialized immune cells responsible for the antiviral response of the host. HTLV-1 cell-free purified viruses can infect dendritic cells in vitro, while T-cell infection is restricted to cell-to-cell transmission. In order to understand the sequence of HTLV-1 dissemination, we undertook a direct comparison of the susceptibilities of the two cell types using cell-associated and cell-free viral sources. We report here that MDDCs are more susceptible to HTLV-1 infection than autologous lymphocytes in vitro and are able to efficiently transmit the virus to lymphocytes. Our results suggest that DCs may represent a true viral reservoir, as the first cell type to be infected in vivo.H uman T-cell leukemia virus type 1 (HTLV-1) infects 5 to 20 million people worldwide (1) and is the etiological agent of both an aggressive CD4 ϩ T-cell leukemia named adult T-cell leukemia (ATL) (2) and a neurological disease named tropical spastic paraparesis/HTLV-1-associated myelopathy (TSP/HAM) (3, 4). HTLV-1 is transmitted through contact with infected cells present in maternal milk, semen, or blood and is mainly found in CD4 ϩ T cells, but other cell types might also be infected or functionally altered in vivo and thus involv...

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Double Stranded RNA‐Dependent Protein Kinase is Necessary for TNF‐α‐Induced Osteoclast Formation In Vitro and In Vivo

Shinohara

Teramachi

Okamura

et al. 2015

J of Cellular Biochemistry

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Double-stranded RNA-dependent protein kinase (PKR) is involved in cell cycle progression, cell proliferation, cell differentiation, tumorgenesis, and apoptosis. We previously reported that PKR is required for differentiation and calcification in osteoblasts. TNF-α plays a key role in osteoclast differentiation. However, it is unknown about the roles of PKR in the TNF-α-induced osteoclast differentiation. The expression of PKR in osteoclast precursor RAW264.7 cells increased during TNF-α-induced osteoclastogenesis. The TNF-α-induced osteoclast differentiation in bone marrow-derived macrophages and RAW264.7 cells was markedly suppressed by the pretreatment of PKR inhibitor, 2-aminopurine (2AP), as well as gene silencing of PKR. The expression of gene markers in the differentiated osteoclasts including TRAP, Calcitonin receptor, cathepsin K, and ATP6V0d2 was also suppressed by the 2AP treatment. Bone resorption activity of TNF-α-induced osteoclasts was also supressed by 2AP treatment. Inhibition of PKR supressed the TNF-α-induced activation of NF-κB and MAPK in RAW264.7 cells. 2AP inhibited both the nuclear translocation of NF-κB and its transcriptional activity in RAW264.7 cells. 2AP inhibited the TNF-α-induced expression of NFATc1 and c-fos, master transcription factors in osteoclastogenesis. TNF-α-induced nuclear translocation of NFATc1 in mature osteoclasts was clearly inhibited by the 2AP treatment. The PKR inhibitor C16 decreased the TNF-α-induced osteoclast formation and bone resorption in mouse calvaria. The present study indicates that PKR is necessary for the TNF-α-induced osteoclast differentiation in vitro and in vivo.

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Alpha Interferon Restricts Human T-Lymphotropic Virus Type 1 and 2 De Novo Infection through PKR Activation

Cited by 28 publications

References 70 publications

How Does Susceptibility to HTLV-1 Infection Varies With the Maturation State of Dendritic Cells?

How Does Susceptibility to HTLV-1 Infection Varies With the Maturation State of Dendritic Cells?

Viral Source-Independent High Susceptibility of Dendritic Cells to Human T-Cell Leukemia Virus Type 1 Infection Compared to That of T Lymphocytes

Double Stranded RNA‐Dependent Protein Kinase is Necessary for TNF‐α‐Induced Osteoclast Formation In Vitro and In Vivo

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