Dendritic cell maturation, but not type I interferon exposure, restricts infection by HTLV-1, and viral transmission to T-cells.

Gergès Rizkallah,Renaud Mahieux,Nicolas Futsch,Chloé Journo,Sandrine Alais,Yuetsu Tanaka,Hélène Dutartre

doi:10.1371/journal.ppat.1006353

Abstract

Human T lymphotropic Virus type 1 (HTLV-1) is the etiological agent of Adult T cell Leukemia/Lymphoma (ATLL) and HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP). Both CD4+ T-cells and dendritic cells (DCs) infected with HTLV-1 are found in peripheral blood from HTLV-1 carriers. We previously demonstrated that monocyte-derived IL-4 DCs are more susceptible to HTLV-1 infection than autologous primary T-cells, suggesting that DC infection precedes T-cell infection. However, during blood transmission, breast-feeding or sexual transmission, HTLV-1 may encounter different DC subsets present in the blood, the intestinal or genital mucosa respectively. These different contacts may impact HTLV-1 ability to infect DCs and its subsequent transfer to T-cells. Using in vitro monocyte-derived IL-4 DCs, TGF-β DCs and IFN-α DCs that mimic DCs contacting HTLV-1 in vivo, we show here that despite their increased ability to capture HTLV-1 virions, IFN-α DCs restrict HTLV-1 productive infection. Surprisingly, we then demonstrate that it is not due to the antiviral activity of type–I interferon produced by IFN-α DCs, but that it is likely to be linked to a distinct trafficking route of HTLV-1 in IL-4 DCs vs. IFN-α DCs. Finally, we demonstrate that, in contrast to IL-4 DCs, IFN-α DCs are impaired in their capacity to transfer HTLV-1 to CD4 T-cells, both after viral capture and trans-infection and after their productive infection. In conclusion, the nature of the DCs encountered by HTLV-1 upon primo-infection and the viral trafficking route through the vesicular pathway of these cells determine the efficiency of viral transmission to T-cells, which may condition the fate of infection.

Highlights

Human T-Lymphotropic Virus type 1 (HTLV-1) infects 5–10 million people [1]
HTLV-1 viruses harboring mutations in the p12 and p30 regulatory genes that have lost their ability to infect human DCs, have an impaired ability to infect macaques [15]. These in vivo experiments strongly suggest that infection of DCs is required for the establishment and maintenance of HTLV-1 infection in animal models. Consistent with these data, we recently showed that human monocytes-derived dendritic cells (MDDCs) are more susceptible to HTLV-1 infection than autologous lymphocytes in vitro [9], supporting a model where DC infection represents an important step upon primo-infection in vivo
We demonstrate that IL-4 DCs and to a lesser extent TGF-β DCs are susceptible to HTLV-1 infection, while IFN-α DCs are not

Summary

Introduction

Human T-Lymphotropic Virus type 1 (HTLV-1) infects 5–10 million people [1]. HTLV-1 is mainly present in Japan, inter-tropical Africa, the Caribbean and South America [2,3]. The role of DC infection in HTLV-1 dissemination to T-cells has been investigated in mice exposed to chimeric HTLV-1-infected cells, in which the HTLV-1 envelope had been replaced by that of the Moloney murine leukemia virus, to allow HTLV-1 to enter murine cells. HTLV-1 viruses harboring mutations in the p12 and p30 regulatory genes that have lost their ability to infect human DCs, have an impaired ability to infect macaques [15] These in vivo experiments strongly suggest that infection of DCs is required for the establishment and maintenance of HTLV-1 infection in animal models. Consistent with these data, we recently showed that human monocytes-derived dendritic cells (MDDCs) are more susceptible to HTLV-1 infection than autologous lymphocytes in vitro [9], supporting a model where DC infection represents an important step upon primo-infection in vivo

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Conclusion