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.

中文翻译：

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HIV-1在髓样靶细胞中的细胞间传播摆脱了SAMHD1的限制。

树突状细胞（DCs）和巨噬细胞以及破骨细胞（OCs）逐渐成为HIV-1的靶细胞，参与病毒的传播，传播和建立持久性组织病毒库。尽管这些髓样细胞由于无细胞病毒的高表达水平而受到无细胞病毒的感染，但我们在这里显示HIV-1使用一种特定且通用的细胞间融合机制进行病毒转移和传播从感染的T淋巴细胞到骨髓谱系的靶细胞，包括未成熟的DC（iDC），OC和巨噬细胞，但不包括单核细胞和成熟的DC。与受感染的T细胞建立联系会导致异型细胞融合，从而将病毒物质快速大量转移到OC和iDC目标中，随后触发与未感染的邻近OC和iDC的同型融合，以进行病毒传播。这两个细胞间的融合过程不受SAMHD1的限制，并允许病毒在髓样细胞中非常有效地传播，从而形成了高病毒产量的多核巨细胞。这些结果揭示了通过在HIV-1感染患者的淋巴组织和非淋巴组织中体内观察到的感染多核巨细胞的形成，使髓样细胞靶标中HIV-1的SAMHD1独立细胞间传播的细胞机制。我们证明，HIV-1使用常见的两步式细胞间融合机制，将大量病毒从受感染的T淋巴细胞转移并传播至髓样靶细胞，包括树突状细胞和巨噬细胞以及破骨细胞。这种细胞间感染过程绕过了SAMHD1宿主细胞限制因子对HIV-1复制施加的限制，导致在HIV-1淋巴组织和非淋巴组织中体内观察到高病毒产生的多核巨细胞的形成感染的患者。由于髓样细胞正在成为HIV-1的重要靶细胞，因此这些结果有助于人们更好地了解这些髓样细胞在发病机理中的作用，包括细胞相关病毒的性传播，细胞间病毒的传播和建立。寿命长的病毒组织储库。导致在HIV-1感染患者的淋巴组织和非淋巴组织中体内观察到高病毒产生的多核巨细胞的形成。由于髓样细胞正在成为HIV-1的重要靶细胞，因此这些结果有助于人们更好地了解这些髓样细胞在发病机理中的作用，包括细胞相关病毒的性传播，细胞间病毒的传播和建立。寿命长的病毒组织储库。导致在HIV-1感染患者的淋巴组织和非淋巴组织中体内观察到高病毒产生的多核巨细胞的形成。由于髓样细胞正在成为HIV-1的重要靶细胞，因此这些结果有助于人们更好地了解这些髓样细胞在发病机理中的作用，包括细胞相关病毒的性传播，细胞间病毒的传播和建立。寿命长的病毒组织储库。