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    HIV-1 cell-to-cell dissemination: cell-fusion to escape antiviral restriction

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    Study directed by Serge Benichou (team of Clotilde Randriamampita)

    HIV-1 cell-to-cell dissemination: cell-fusion to escape antiviral restriction

    Like CD4 T lymphocytes, myeloid cells including macrophages, dendritic cells, but also bone osteoclasts, are target cells of the human immunodeficiency virus HIV-1. While the mechanisms for intercellular dissemination of HIV-1 in these myeloid cells have been poorly investigated, the recent study of Serge Benichou's group (Team C. Randriamampita) published in mBio, has shown that HIV-1 is massively transferred from infected CD4 T cells to these myeloid cells through a two-step cell fusion process, leading to the formation of highly virus-productive multinucleated giant cells.

     

    As CD4+ T lymphocytes, dendritic cells (DCs), macrophages as well as bone osteoclasts (OCs) are emerging as target cells of HIV-1 involved in virus transmission, dissemination, and establishment of persistent tissue virus reservoirs. While these myeloid cells are poorly infected by cell-free viruses, because of the high expression of cellular restriction factorssuch as SAMHD1, the study performed in the group of Serge Benichou in collaboration with the group of Christel Verollet (CNRS, Toulouse), shows that HIV-1 uses a specific and common cell-to-cell fusion mechanism for virus transfer and dissemination from infected T lymphocytes to the target cells of the myeloid lineage, including immature DCs, OCs and macrophages, but not monocytes and mature DCs.

     

    The establishment of contacts with infected T cells leads to heterotypic cell fusion for the fast and massive transfer of viral material into OC and iDC targets, which subsequently triggers homotypic fusion with non-infected neighboring OCs and iDCs for virus dissemination. This cell-to-cell infection process by cell-fusion bypasses the restriction imposed by the SAMHD1 host cell restriction factor for HIV-1 replication leading to the formation of highly virus-productive multinucleated giant cells as observed in vivo in lymphoid and non-lymphoid tissues of HIV-1-infected patients. 

     

     

    Figure: Multinucleated giant cell issued from fusion between HIV-1 infected T cells and dendritic cells. Nuclei are in blue, HIV-1 infection (gag protein) is labeled in green, and the CD3 T-cell-specific marker is in pink.

     

     

     

     

    Since myeloid cells are emerging as important target cells of HIV-1, these results contribute to a better understanding of the role of these myeloid cells in pathogenesis, including cell-associated virus sexual transmission, cell-to-cell virus spreading, and establishment of long-lived viral tissue reservoirs.

     

    Reference

    Xie M, Leroy H, Mascarau R, Woottum M, Dupont M, Ciccone C, Schmitt A, Raynaud- Messina B, Vérollet C, Bouchet J, Bracq L, Benichou S. 2019. Cell-to-cell spreading of HIV- 1 in myeloid target cells escapes SAMHD1 restriction. mBio 10:e02457-19.

     

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