T Cell-Macrophage Fusion Triggers Multinucleated Giant Cell Formation for HIV-1 Spreading

Abstract

HIV-1-infected macrophages participate in virus dissemination and establishment of virus reservoirs in host tissues, but the mechanisms for virus cell-to-cell transfer to macrophages remain unknown. Here, we reveal the mechanisms for cell-to-cell transfer from infected T cells to macrophages and virus spreading between macrophages. We show that contacts between infected T lymphocytes and macrophages lead to cell fusion for fast and massive transfer of CCR5-tropic viruses to macrophages. Through the merge of viral material between T cells and macrophages, these newly formed lymphocyte/macrophage fused cells acquire the ability to fuse with neighboring non-infected macrophages. Together, these two-step envelope-dependent cell fusion processes lead to the formation of highly virus-productive multinucleated giant cells reminiscent of the infected multinucleated giant macrophages detected in HIV-1-infected patients and SIV-infected macaques. These mechanisms represent an original mode of virus transmission for viral spreading and a new model for the formation of macrophage virus reservoirs during infection. We reveal a very efficient mechanism involved in cell-to-cell transfer from infected T cells to macrophages and subsequent virus spreading between macrophages by a two-step cell fusion process. Infected T cells first establish contacts and fuse with macrophage targets. The newly formed lymphocyte/macrophage fused cells then acquire the ability to fuse with surrounding uninfected macrophages leading to the formation of infected multinucleated giant cells that can survive for a long time as evidenced in lymphoid organs and the central nervous system. This route of infection may be a major determinant for virus dissemination and the formation of macrophage virus reservoirs in host tissues during HIV-1 infection.

Bone degradation machinery of osteoclasts: An HIV-1 target that contributes to bone loss

“…Up to now, the presence of HIV-1 in bones has not been documented. As recently shown for macrophages (61), direct contact of OC with infected Jurkat or primary CD4 + T lymphocytes leads to virus transfer and productive infection of OC, which is clearly more efficient than infection by cell-free viruses. This is likely to be the physio-pathological route to infect OC in situ, which would be consistent with data showing that cell-to-cell infection is critical for efficient viral spread in vitro and in vivo (25,29,(61)(62)(63)(64)(65)(66)(67)(68)(69).…”

Kinetic Analysis of the Motility of Giant Virus-Infected Amoebae Using Phase-Contrast Microscopic Images

“…This phenomenon may be an antiviral strategy of the host, similar to Faustovirus-infected amoeba releasing a factor that triggers the encystment of neighbor cells (Borges et al, 2019). Or it may be a viral spreading strategy, similar to the efficient spread of HIV-1 through contact and fusion of host cells (Bracq et al, 2017). Studying the source of the direction bias and the conditions of amoeba cells inside the "bunch" may be helpful to understand the viral infection.…”

Common signalling pathways in macrophage and osteoclast multinucleation

“…Moreover, both MGCs and osteoclasts have been reported to play a role in the pathogenesis of osteoarthritis and rheumatoid arthritis (Weinberg et al, 1993;McInnes and Schett, 2011). MGCs and osteoclasts have also been shown to be a HIV-1 target, suggesting that macrophage multinucleation could contribute to the spreading of the virus (Bracq et al, 2017) and osteoclast-specific bone loss (Raynaud-Messina et al, 2018). Thus macrophage multinucleation could be considered as a basic phenomenon that is perturbed in bone, inflammatory and infectious disorders (Box 3).…”

“…While the exact cause of this pathology is unknown, the disease process initiates when dendritic cells in the vessel wall recruit T-cells and macrophages to fuse and form granulomatous infiltrates (Salvarani et al, 2012). Similarly, T-cell-macrophage fusion results in MGC formation, allowing the spread of human immunodeficiency virus (HIV) (Bracq et al, 2017). MGCs can also form in response to large foreign materials, such as implanted biomedical devices, and they are then designated FBGCs (Anderson, 2000).…”