Cell-to-Cell Spreading of HIV-1 in Myeloid Target Cells Escapes SAMHD1 Restriction

Maorong Xie (1) , Héloïse Leroy (2, 1) , Rémi Mascarau (3) , Marie Woottum (1) , Maeva Dupont (3) , Camille Ciccone (1) , Alain Schmitt (1) , Brigitte Raynaud-Messina (3) , Christel Vérollet (3) , Jerome Bouchet (1) , Lucie Bracq (1) , Serge Benichou (4)

1 IC UM3 (UMR 8104 / U1016) - Institut Cochin
2 IC UM3 (UMR 8104 / U1016) - Institut Cochin
3 IPBS - Institut de pharmacologie et de biologie structurale
4 [Institut Cochin] Departement Infection, immunité, inflammation

Dendritic cells (DCs) and macrophages as well as 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 levels of cellular restriction factors such as SAMHD1, we show here 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 (iDCs), 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 noninfected neighboring OCs and iDCs for virus dissemination. These two cell-to-cell fusion processes are not restricted by SAMHD1 and allow very efficient spreading of virus in myeloid cells, resulting in the formation of highly virus-productive multinucleated giant cells. These results reveal the cellular mechanism for SAMHD1-independent cell-to-cell spreading of HIV-1 in myeloid cell targets through the formation of the infected multinucleated giant cells observed in vivo in lymphoid and nonlymphoid tissues of HIV-1-infected patients. IMPORTANCE We demonstrate that HIV-1 uses a common two-step cell-to-cell fusion mechanism for massive virus transfer from infected T lymphocytes and dissemination to myeloid target cells, including dendritic cells and macrophages as well as osteoclasts. This cell-to-cell infection process 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 nonlymphoid tissues of HIV-1-infected patients. 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.

Mots clés: HIV-1; SAMHD1; cell fusion; myeloid cells; virus spreading

Domaines: Sciences du Vivant [q-bio]

Maorong Xie, Héloïse Leroy, Rémi Mascarau, Marie Woottum, Maeva Dupont, et al.. Cell-to-Cell Spreading of HIV-1 in Myeloid Target Cells Escapes SAMHD1 Restriction. mBio, 2019, 10, ⟨10.1128/mbio.02457-19⟩. ⟨hal-03030549⟩