HTLV-1 Evades Type I Interferon Antiviral Signaling by Inducing the Suppressor of Cytokine Signaling 1 (SOCS1)

Human T cell leukemia virus type 1 (HTLV-1) is the etiologic agent of Adult T cell Leukemia (ATL) and the neurological disorder HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Although the majority of HTLV-1–infected individuals remain asymptomatic carriers (AC) during their lifetime, 2–5% will develop either ATL or HAM/TSP, but never both. To better understand the gene expression changes in HTLV-1-associated diseases, we examined the mRNA profiles of CD4+ T cells isolated from 7 ATL, 12 HAM/TSP, 11 AC and 8 non-infected controls. Using genomic approaches followed by bioinformatic analysis, we identified gene expression pattern characteristic of HTLV-1 infected individuals and particular disease states. Of particular interest, the suppressor of cytokine signaling 1—SOCS1—was upregulated in HAM/TSP and AC patients but not in ATL. Moreover, SOCS1 was positively correlated with the expression of HTLV-1 mRNA in HAM/TSP patient samples. In primary PBMCs transfected with a HTLV-1 proviral clone and in HTLV-1-transformed MT-2 cells, HTLV-1 replication correlated with induction of SOCS1 and inhibition of IFN-α/β and IFN-stimulated gene expression. Targeting SOCS1 with siRNA restored type I IFN production and reduced HTLV-1 replication in MT-2 cells. Conversely, exogenous expression of SOCS1 resulted in enhanced HTLV-1 mRNA synthesis. In addition to inhibiting signaling downstream of the IFN receptor, SOCS1 inhibited IFN-β production by targeting IRF3 for ubiquitination and proteasomal degradation. These observations identify a novel SOCS1 driven mechanism of evasion of the type I IFN antiviral response against HTLV-1

New onshore/offshore evidence of the Messinian Erosion Surface from key areas: The Ibiza-Balearic Promontory and the Orosei-Eastern Sardinian margin

As the Messinian sea-level draw down associated with the Messinian Salinity Crisis is still questioned, we propose to show that the widely spread erosion surface affecting the Mediterranean margins is indeed linked to an exondation demonstrated from offshore and onshore data. Our study presents a comprehensive onshore to offshore correlation of the Messinian erosional surface. It is focused on small drainage systems or interfluve areas, outside of evaporite basins or incised canyons, where the Messinian erosion had not yet been studied previously: around Ibiza on the Balearic Promontory and around Orosei on the Eastern Sardinian margin, Tyrrhenian Basin, both areas where new offshore data were recently acquired. We show that the late Messinian erosion formed in subaerial settings, as testified by evidence of continentalization events, and attests for a regression phase that was correlated from the offshore continental slopes to the onshore paleo-platforms in both areas. Characteristics of this erosion in both study areas strengthen the scenario with at least one important low-stand sea-level for the Messinian Salinity Crisis with evaporites subbasins lying at different depths and possibly disconnected.Depuis la découverte de la crise de salinité messinienne dans les années 70, le scénario proposant une chute importante du niveau marin associé à la mise en place des évaporites dans les plaines abyssales de la Méditerranée est régulièrement remis en cause. Nous montrons que la surface d’érosion affectant l’ensemble des marges est en effet liée à une émersion que l’on peut suivre à terre. Les observations présentées à terre s’attachent aux zones d’interfluves en dehors des bassins évaporitiques périphériques, là où la surface d’érosion messinienne n’a pas été étudiée : autour de l’île d’Ibiza dans les Baléares et autour d’Orosei sur la marge est-sarde. La surface d’érosion messinienne y est mise en évidence pour la première fois. Les données de sismique haute résolution récemment acquises dans ces deux zones nous permettent de présenter des corrélations terre-mer. Des évènements marquant clairement une continentalisation caractérisent la limite Mio-Pliocène dans les deux régions et atteste une phase régressive que l’on peut suivre des paléo-plateformes continentales à terre aux pentes du domaine offshore. Ces observations apportent des éléments pour étayer un scénario de la crise avec un bas niveau marin et des bassins évaporitiques à différentes paléo-bathymétries, possiblement déconnectés les uns des autres

Increased proviral load in HTLV-1-infected patients with rheumatoid arthritis or connective tissue disease.

BACKGROUND: Human T-lymphotropic virus type 1 (HTLV-1) proviral load is related to the development of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and has also been shown to be elevated in the peripheral blood in HTLV-1-infected patients with uveitis or alveolitis. Increased proliferation of HTLV-1-infected cells in, or migration of such cells into, the central nervous system is also seen in HAM/TSP. In the present study, we evaluated the proviral load in a cohort of HTLV-1-infected patients with arthritic conditions. RESULTS: HTLV-1 proviral load in the peripheral blood from 12 patients with RA and 6 patients with connective tissue disease was significantly higher than that in matched asymptomatic HTLV-1 carriers, but similar to that in matched HAM/TSP controls. HAM/TSP was seen in one-third of the HTLV-1-infected patients with RA or connective tissue disease, but did not account for the higher proviral load compared to the asymptomatic carrier group. The proviral load was increased in the synovial fluid and tissue from an HTLV-1-infected patient with RA, the values suggesting that the majority of infiltrated cells were HTLV-1-infected. In the peripheral blood from HTLV-1-infected patients with RA or connective tissue disease, HTLV-1 proviral load correlated with the percentages of memory CD4+ T cells and activated T cells, and these percentages were shown to be markedly higher in the synovial fluid than in the peripheral blood in an HTLV-1-infected patient with RA. CONCLUSIONS: These biological findings are consistent with a role of the retrovirus in the development of arthritis in HTLV-1-infected patients. A high level of HTLV-1-infected lymphocytes in the peripheral blood and their accumulation in situ might play a central role in the pathogenesis of HTLV-1-associated inflammatory disorders. Alternatively, the autoimmune arthritis, its etiological factors or treatments might secondarily enhance HTLV-1 proviral load

New constraints on the Messinian salinity crisis from the north-eastern Ibiza island event records

International audienceIn order to better constrain the chronology of the Messinian Salinity Crisis (MSC) onland and to provide new observations on the stratigraphic position of the Messinian erosional surface as well as evidence for continentalization, we have studied the Mio-Pleistocene succession of the island of Ibiza, ideally located in a strategic position between the peripheral Messinian basins of south-eastern Spain and the MSC-related gypsum of the Palma Basin (Mallorca). Five lithological units are identified and compared with those known from the island of Mallorca. The equivalent of the "reef" unit, mainly Tortonian in age, is composed of median to inner ramp facies. It is overlain by coastal alluvial fans set up under extensive tectonic control, and then by a carbonate unit rich in oolites and microbialites attributed to the Terminal Carbonate Complex (TCC) of Messinian age. The overlying red clays fossilizing paleosols express a continentalization phase at the end of the Miocene. This regressive episode is evidenced by karstification and erosion incising the pre-crisis units and shaping valleys connected to submarine canyons. The erosion surface is linked to the acme of the MSC, a major sea-level fall, and is then sealed by Pliocene coastal calcarenites or by Pleistocene eolianites. The emptying of the basin led to a global collapse, which is recorded on all the slope domains of the Mediterranean margins. We document this collapse for the first time onland by syn-MSC gravity events such as mudflows, upwelling of geothermal fluids under pressure and soft deformation of the TCC. The interweaving of these phenomena of multiple origin (baselevel decrease, climate change, geothermal activity, sediment transfer) contributes to the onland/offshore reshaping of the Mediterranean margins during the major environmental changes of the Messinian salinity crisis