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Human T-Lymphotropic virus type 1 (HTLV-1) is the causative agent of two distinctpathologies, adult T-cell leukemia (ATL), an aggressive malignancy of matureCD4+ T-cells, and tropical spastic paraparesis/HTLV-1-associated myelopathy(TSP/HAM), a demyelinating neurodegenerative disease. An estimated 10–20million people worldwide are infected with HTLV-1. While the majority of HTLV-1-infected individuals remain asymptomatic, a low percentage of patients developeither ATL (3–5%) or TSP/HAM (0.3–2%) after a long period of clinical latency.HTLV-1 primarily infects CD4+ T-cells and has been detected in ex vivo CD8+Tcells,B-cells, monocytes and dendritic cells (DC) from infected individuals. Thesecells may contribute, more than previously thought, to viral persistence andpathogenesis. DCs isolated from HTLV-1-positive patients are defective in IFN- response upon in vitro stimulation and their ability to activate T-cells is impaired. Inaddition, in HTLV-1 infected patients alteration in monocytes differentiation andactivation has been reported. Contrarily to how observed in T or B cell, whereHTLV-1 p30 is not required in vitro for an efficient viral replication, p30 seems toplay a key role during HTLV-1 infection of DCs. In the macaque model, the ablationof p30 expression within the HTLV-1 provirus (p30-KO) or p12/p8 (p12-KO)severely affects infectivity. Furthermore, the infectivity of p30-KO in human primarymonocyte-derived dendritic cells (Mo-mDCs) is severely impaired and is notsustained over time. Prior data demonstrated that p30, by interacting with thecellular transcription factor PU.1 in human monocytes, affects TLR4 signaling andthe expression of several genes involved in apoptosis, cell cycle, and transcription,pointing to p30 as a regulator of innate response to HTLV-1. The interaction of p30and PU.1 might lead to inhibition of the transcriptional activity of PU.1.We used a human monocytic cell line, THP-1 and primary dendritic cells, to studythe mechanism of p30 and p12/p8 requirement in these cell types. Wehypothesized that p30 and/or p12/p8 affected not only TLR3/4 but also TLR7/8signaling in virus infected monocytes and in dendritic cells, and that by affecting thetype 1 IFN response p30 and/or p12/p8 affects the activation and differentiation ofthese cells and ultimately the host response to the virus allowing viral replicationand spread throughout the body.We confirm that p30 decreases the expression of TLR4 on THP-1 surface and theproduction of IL12 and TNF by these cells. p30 is also able to inhibit theexpression of interferon responsive genes (ISG) following stimulation with LPS ofthe TLR4 and with polyI:C of TLR3, but not of TLR7/8 with Imiquimod. Resultsin THP-1 mirrored those in ex-vivo human primary monocyte-derived dendritic cells(Mo-mDC). The effect of p30 on TLRs signaling was also demonstrated by ablatingits expression within a molecular clone of HTLV-1. HTLV-1 infection ofmonocytes inhibited TLR3 and TLR4–induced ISGs…

Role of HTLV-1 p30 during infection of monocytes and dendritic cells