M-Sec induced by HTLV-1 mediates an efficient viral transmission.

Masateru Hiyoshi,Naofumi Takahashi,Takaharu Ueno,Yuetsu Tanaka,Atae Utsunomiya,Seiji Okada,Youssef M Eltalkhawy,Yuko Sato,Tadaki Suzuki,Osamu Noyori,Jutatip Panaampon,Sameh Lotfi,Yorifumi Satou,Hideki Hasegawa,Shinya Suzu,Masao Matsuoka,Masahito Tokunaga,Jun‐Ichi Fujisawa ,Jun‐Ichirou Yasunaga

doi:10.1371/journal.ppat.1010126

Abstract

Human T-cell leukemia virus type 1 (HTLV-1) infects target cells primarily through cell-to-cell routes. Here, we provide evidence that cellular protein M-Sec plays a critical role in this process. When purified and briefly cultured, CD4+ T cells of HTLV-1 carriers, but not of HTLV-1- individuals, expressed M-Sec. The viral protein Tax was revealed to mediate M-Sec induction. Knockdown or pharmacological inhibition of M-Sec reduced viral infection in multiple co-culture conditions. Furthermore, M-Sec knockdown reduced the number of proviral copies in the tissues of a mouse model of HTLV-1 infection. Phenotypically, M-Sec knockdown or inhibition reduced not only plasma membrane protrusions and migratory activity of cells, but also large clusters of Gag, a viral structural protein required for the formation of viral particles. Taken together, these results suggest that M-Sec induced by Tax mediates an efficient cell-to-cell viral infection, which is likely due to enhanced membrane protrusions, cell migration, and the clustering of Gag.

Highlights

M-Sec is a key regulator of the formation of plasma membrane protrusions including tunneling nanotubes, the F-actin-containing long plasma membrane extensions [1,2], and plays a critical role in initiating the protrusions or extensions [3,4]
We identified the cellular protein M-Sec as a host factor necessary for de novo infection of human T-cell leukemia virus type 1 (HTLV-1), the causative retrovirus of an aggressive blood cancer known as adult T-cell leukemia/lymphoma
The inhibition or knockdown of M-Sec in infected cells resulted in a reduced viral infection in several culture models and a mouse model

Summary

Introduction

M-Sec ( known as TNF-α-induced protein 2, TNFAIP2) is a key regulator of the formation of plasma membrane protrusions including tunneling nanotubes, the F-actin-containing long plasma membrane extensions [1,2], and plays a critical role in initiating the protrusions or extensions [3,4]. Small molecule compound that inhibits M-Sec-induced membrane protrusions reduced HIV-1 production in monocyte-derived macrophages [8]. The knockdown of M-Sec retarded HIV-1 production in U87 glioma cells [9], a widely-used HIV-1 target cell line. As M-Sec inhibition or knockdown reduces membrane protrusions and cell migration in these cells [8,9], M-Sec appears to contribute to the initial phase of HIV-1 transmission by enhancing membrane protrusions and cell migration. The widely used CD4+ T cell line Jurkat was negative for M-Sec expression, which was the case even after productive HIV-1 replication in the cells [8]. M-Sec is thought not to be related to the cell-to-cell transmission of human T-cell leukemia virus type 1 (HTLV-1), another human retrovirus that preferentially infects CD4+ T cells

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Results

Discussion

Conclusion