Human T-Cell Leukemia/Lymphoma Virus Type 1 p30, but Not p12/p8, Counteracts Toll-Like Receptor 3 (TLR3) and TLR4 Signaling in Human Monocytes and Dendritic Cells

Fenizia, Claudio; Fiocchi, Martina; Jones, Kathryn; Parks, Robyn Washington; Ceribelli, Michele; Chevalier, Sébastien Alain; Edwards, Dustin; Ruscetti, Francis W.; Pise-Masison, Cynthia A.; Franchini, Genoveffa

doi:10.1128/jvi.01788-13

Cited by 32 publications

(38 citation statements)

References 54 publications

(70 reference statements)

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“…We have previously demonstrated that the abrogation of orf-I expression results in loss of HTLV-1 infectivity of primary monocyte-derived dendritic cells [18] and further that infection of the monocytic cell line THP-1 mirrored results of ex vivo , primary dendritic cells [25]. To define the relative contribution of p8, p12, or both to monocyte infection, we exposed the monocytic cell line THP-1 to equivalent amounts of virus as measured by p19Gag from unfiltered cell-free supernatants.…”

Section: Resultsmentioning

confidence: 95%

Co-dependence of HTLV-1 p12 and p8 Functions in Virus Persistence

et al. 2014

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HTLV-1 orf-I is linked to immune evasion, viral replication and persistence. Examining the orf-I sequence of 160 HTLV-1-infected individuals; we found polymorphism of orf-I that alters the relative amounts of p12 and its cleavage product p8. Three groups were identified on the basis of p12 and p8 expression: predominantly p12, predominantly p8 and balanced expression of p12 and p8. We found a significant association between balanced expression of p12 and p8 with high viral DNA loads, a correlate of disease development. To determine the individual roles of p12 and p8 in viral persistence, we constructed infectious molecular clones expressing p12 and p8 (D26), predominantly p12 (G29S) or predominantly p8 (N26). As we previously showed, cells expressing N26 had a higher level of virus transmission in vitro. However, when inoculated into Rhesus macaques, cells producing N26 virus caused only a partial seroconversion in 3 of 4 animals and only 1 of those animals was HTLV-1 DNA positive by PCR. None of the animals exposed to G29S virus seroconverted or had detectable viral DNA. In contrast, 3 of 4 animals exposed to D26 virus seroconverted and were HTLV-1 positive by PCR. In vitro studies in THP-1 cells suggested that expression of p8 was sufficient for productive infection of monocytes. Since orf-I plays a role in T-cell activation and recognition; we compared the CTL response elicited by CD4+ T-cells infected with the different HTLV-1 clones. Although supernatant p19 levels and viral DNA loads for all four infected lines were similar, a significant difference in Tax-specific HLA.A2-restricted killing was observed. Cells infected with Orf-I-knockout virus (12KO), G29S or N26 were killed by CTLs, whereas cells infected with D26 virus were resistant to CTL killing. These results indicate that efficient viral persistence and spread require the combined functions of p12 and p8.

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Section: Resultsmentioning

confidence: 95%

Co-dependence of HTLV-1 p12 and p8 Functions in Virus Persistence

et al. 2014

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“…In addition, SAMHD1 expression has been shown to be regulated by interferons (86)(87)(88)(89). We recently showed that expression of the HTLV-1 p30 protein dampens interferon responses in monocytes and dendritic cells by blocking the expression of interferon-responsive genes (40). Thus, more studies are needed to determine whether HTLV-1 preferentially infects SAMHD1-negative monocytes in vivo, what role HTLV-1 regulatory proteins play, and how SAMHD1 is regulated in different cell types.…”

Section: Discussionmentioning

confidence: 99%

“…Monocytes are precursors of tissue macrophages and dendritic cells and play a central role in the immune response to pathogens. Monocytes can be infected in vitro and in vivo by HTLV-1 (26,29,30,(33)(34)(35)(36)(37)(38)(39)(40). Furthermore, studies with nonhuman primates indicate that monocyte infection, which depends on the expression of the viral orf-I-encoded p8 and p12 proteins and the viral p30 protein, is pivotal for viral infectivity and persistence in vivo (38,40,41).…”

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confidence: 99%

“…Monocytes can be infected in vitro and in vivo by HTLV-1 (26,29,30,(33)(34)(35)(36)(37)(38)(39)(40). Furthermore, studies with nonhuman primates indicate that monocyte infection, which depends on the expression of the viral orf-I-encoded p8 and p12 proteins and the viral p30 protein, is pivotal for viral infectivity and persistence in vivo (38,40,41). However, recent in vitro studies by others demonstrated that infection of primary monocytes is abortive due to the expression of the sterile alpha motif and histidine/aspartic acid domain-containing protein 1 (SAMHD1) restriction factor and that, by hydrolyzing endogenous deoxynucleoside triphosphates, it inhibits reverse transcription (RT) (42), calling into question the role of monocytes in viral persistence.…”

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Human T Cell Leukemia Virus Type 1 Infection of the Three Monocyte Subsets Contributes to Viral Burden in Humans

Castro-Amarante

Pise-Masison

McKinnon

et al. 2016

J Virol

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A pproximately 2 to 3% of human T cell leukemia virus type 1 (HTLV-1)-infected individuals develop adult T-cell leukemia/lymphoma (ATL) and another 2 to 3% develop HTLV-1-associated myelopathy (HAM)/tropical spastic paraparesis (TSP) in their lifetimes (1-4). In addition to HAM/TSP (5, 6), HTLV-1 is also associated with other inflammatory conditions, such as uveitis (6) Sjögren's syndrome (7), bronchoalveolitis and arthritis (8), and polymyositis (9). It is noteworthy that some patients present with more than one of these inflammatory conditions (10). HTLV-1 primarily infects CD4 ϩ and CD8 ϩ effector and memory T cells and regulatory CD4 ϩ CD25 ϩ T cells (11,12). A high viral DNA burden in peripheral blood mononuclear cells (PBMCs) is a risk factor for HAM/TSP (13) and ATL development (14-16), and patients with HAM/TSP have a higher virus level in the cerebrospinal fluid (CSF) than in the peripheral blood (12). The virus level alone is not sufficient to differentiate symptomatic patients from healthy carriers, suggesting the importance of other factors, including the host immune response (16)(17)(18)(19)(20). HAM/TSP patients present diverse immunological alterations, such as increased levels of spontaneous lymphocyte proliferation (21, 22), tax-specific cytotoxic CD8 ϩ T cell expansion, and the production of high levels of inflammatory cytokines (23)(24)(25). Several studies have also suggested that monocytes are involved in immune reg-

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“…Datta et al (2006) have also shown that p30 II inhibits DNA-binding by PU.1 and represses (Toll-like receptor-4) TLR4 inflammatory signaling in macrophages. These studies were recently extended by Fenizia et al (2014), who demonstrated that p30 II inhibits the expression of interferon-responsive genes following lipopolysaccharide-stimulation of TLR3 and TLR4 in monocytes and dendritic cells, which may contribute to a permissive cellular phenotype during early-stage infection as well as throughout the course of persistent disease.…”

Section: Discussionmentioning

confidence: 94%

Acetylation of the c-MYC oncoprotein is required for cooperation with the HTLV-1 p30 II accessory protein and the induction of oncogenic cellular transformation by p30 II /c-MYC

Romeo

Kim

et al. 2015

Virology

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The human T-cell leukemia retrovirus type-1 (HTLV-1) p30II protein is a multifunctional latency-maintenance factor that negatively regulates viral gene expression and deregulates host signaling pathways involved in aberrant T-cell growth and proliferation. We have previously demonstrated that p30II interacts with the c-MYC oncoprotein and enhances c-MYC-dependent transcriptional and oncogenic functions. However, the molecular and biochemical events that mediate the cooperation between p30II and c-MYC remain to be completely understood. Herein we demonstrate that p30II induces lysine-acetylation of the c-MYC oncoprotein. Acetylation-defective c-MYC Lys→Arg substitution mutants are impaired for oncogenic transformation with p30II in c-myc−/− HO15.19 fibroblasts. Using dual-chromatin-immunoprecipitations (dual-ChIPs), we further demonstrate that p30II is present in c-MYC-containing nucleoprotein complexes in HTLV-1-transformed HuT-102 T-lymphocytes. Moreover, p30II inhibits apoptosis in proliferating cells expressing c-MYC under conditions of genotoxic stress. These findings suggest that c-MYC-acetylation is required for the cooperation between p30II/c-MYC which could promote proviral replication and contribute to HTLV-1-induced carcinogenesis.

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Human T-Cell Leukemia/Lymphoma Virus Type 1 p30, but Not p12/p8, Counteracts Toll-Like Receptor 3 (TLR3) and TLR4 Signaling in Human Monocytes and Dendritic Cells

Cited by 32 publications

References 54 publications

Co-dependence of HTLV-1 p12 and p8 Functions in Virus Persistence

Co-dependence of HTLV-1 p12 and p8 Functions in Virus Persistence

Human T Cell Leukemia Virus Type 1 Infection of the Three Monocyte Subsets Contributes to Viral Burden in Humans

Acetylation of the c-MYC oncoprotein is required for cooperation with the HTLV-1 p30 II accessory protein and the induction of oncogenic cellular transformation by p30 II /c-MYC

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