Abstract
HIV-1 Env mediates fusion of viral and target cell membranes, but it can also mediate fusion of infected (producer) and target cells, thus triggering the formation of multinucleated cells, so-called syncytia. Large, round, immobile syncytia are readily observable in cultures of HIV-1-infected T cells, but these fast growing “fusion sinks” are largely regarded as cell culture artifacts. In contrast, small HIV-1-induced syncytia were seen in the paracortex of peripheral lymph nodes and other secondary lymphoid tissue of HIV-1-positive individuals. Further, recent intravital imaging of lymph nodes in humanized mice early after their infection with HIV-1 demonstrated that a significant fraction of infected cells were highly mobile, small syncytia, suggesting that these entities contribute to virus dissemination. Here, we report that the formation of small, migratory syncytia, for which we provide further quantification in humanized mice, can be recapitulated in vitro if HIV-1-infected T cells are placed into 3D extracellular matrix (ECM) hydrogels rather than being kept in traditional suspension culture systems. Intriguingly, live-cell imaging in hydrogels revealed that these syncytia, similar to individual infected cells, can transiently interact with uninfected cells, leading to rapid virus transfer without cell-cell fusion. Infected cells were also observed to deposit large amounts of viral particles into the extracellular space. Altogether, these observations suggest the need to further evaluate the biological significance of small, T cell-based syncytia and to consider the possibility that these entities do indeed contribute to virus spread and pathogenesis.
Highlights
Human immunodeficiency virus type 1 (HIV-1) primarily infects CD4+ T lymphocytes and macrophages
The spread of virus between infected and susceptible target cells can take place via several pathways, including: release of cell-free virus particles which are stochastically encountered by a target cell; sequestration of virus particles by dendritic cells and subsequent delivery of these particles to a target cell; and the process of cell-to-cell transmission, whereby an infected cell directly interacts with a target cell, forming a transient adhesion structure known as the virological synapse (VS; [2,3]), which facilitates transfer of newly released viral particles
Syncytia, which are multinucleated entities that form when Env-expressing cells fuse with target cells, were considered to be artifacts of cell culture and/or were thought to occur in infected individuals only if HIV-1-infected dendritic cells or macrophages occasionally fuse with target T cells
Summary
Human immunodeficiency virus type 1 (HIV-1) primarily infects CD4+ T lymphocytes and macrophages. The spread of virus between infected and susceptible target cells can take place via several pathways, including: release of cell-free virus particles which are stochastically encountered by a target cell; sequestration of virus particles by dendritic cells and subsequent delivery of these particles to a target cell (a process termed trans-infection [1]); and the process of cell-to-cell transmission, whereby an infected cell directly interacts with a target cell, forming a transient adhesion structure known as the virological synapse (VS; [2,3]), which facilitates transfer of newly released viral particles Such interactions are thought to occur most frequently in secondary lymphoid tissue, such as in lymph nodes and the gut-associated lymphoid tissue (GALT), where high cell density and migratory scanning behavior of T cells, facilitated by the architecture of the stromal environment, provide conditions conducive to controlled cell–cell interactions, including antigen presentation through the immunological synapse [4,5,6,7]. As will be described in the following, observations made in lymph nodes of HIV-1-infected humanized mice [20], together with two (largely ignored) earlier reports that documented lymphocyte-based small syncytia in secondary lymphoid tissue of infected individuals [21,22], forced us to reconsider the significance of HIV-1-induced T lymphocyte-based syncytia
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