Infected myeloid cells, especially macrophages, are found as multinucleated giant cells (MGCs Compton and Schwartz, 2017 Orenstein, 2000 Verollet et al., 2010), in diverse tissues of HIV-infected patients ( Rodrigues et al., 2017 Sattentau and Stevenson, 2016), including lymph nodes, spleen, lungs, genital, digestive tracts, and the brain. In addition, a delayed viral rebound was observed in the context of combination of antiretroviral therapy (cART) in a model of humanized mice reconstituted with only myeloid cells, consistent with the establishment of persistent infection in tissue macrophages ( Honeycutt et al., 2017). Animal models of infection such as Simian Immunodeficiency Virus (SIV)-infected macaques and HIV-1-infected humanized mice further support in vivo infection of macrophages ( Arainga et al., 2017 Avalos et al., 2017 DiNapoli et al., 2017 Honeycutt et al., 2017). Whereas most of HIV-infected CD4 + T cells die within a few days of infection, in vitro studies suggest that HIV-1-infected macrophages developed mechanisms to limit cell death, resulting in viral replication for extended periods of time. They are one of the primary targets for HIV-1 in vivo, as they express the viral CD4 receptor and the chemokine coreceptors CCR5 and CXCR4, although at a lower level than CD4 + T cells. Our study provides important insights into the mechanisms underlying infection of tissue-resident macrophages, and establishment of persistent cellular reservoirs in patients.Īlthough CD4 + T lymphocytes are considered as the main targets of HIV infection, macrophages also play a significant role in HIV-1 infection and contribute to viral persistence and pathogenesis ( Hendricks et al., 2021 Sattentau and Stevenson, 2016). This fusion process engages a specific short-lived adhesion structure and is controlled by the CD81 tetraspanin, which activates RhoA/ROCK-dependent actomyosin contractility in macrophages. We also find that this mode of infection is modulated by the macrophage polarization state. Importantly, several tissue macrophage populations undergo this heterotypic cell fusion, including synovial, placental, lung alveolar, and tonsil macrophages.
Here, we demonstrate that fusion of infected CD4 + T lymphocytes with human macrophages leads to their efficient and productive infection. Although cell-to-cell transmission of HIV-1 is a determinant mode of macrophage infection in vivo, how HIV-1 transfers toward macrophages remains elusive. Therefore, it is critical to understand macrophage infection, especially in tissue macrophages, which are widely infected in vivo, but poorly permissive to cell-free infection. Macrophages are essential for HIV-1 pathogenesis and represent major viral reservoirs.
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