HIV-1 cell-to-cell spread overcomes the virus entry block of non-macrophage-tropic strains in macrophages

Understanding how HIV-1 hijacks the functions of immune cells to promote viral spreading remains a challenge in the fight against infection. MΦ are ubiquitous tissue-resident cells, involved in tissue homeostasis and immunity. In HIV-1 infection, along with CD4+ T lymphocytes, MΦ serve as vectors for virus dissemination and as viral reservoirs, impeding HIV-1 eradication. However, the mechanisms of their infection remain incompletely understood. A paradox is that infected MΦ are found in a large range of tissues whereas in vitro cellular tropism assays indicate that only a limited number of HIV-1 isolates can enter MΦ. We hypothesized that these assays, which evaluate infection using cell-free viruses, might not fully reflect the modes of MΦ infection in patients. We report here that virus cell-to-cell transfer through cell-cell fusion with infected CD4+ T cells is a very effective means of infecting MΦ, even with virus isolates characterized as non-macrophage tropic in cell-free infection. This intercellular viral transfer is facilitated by enhanced interactions between the HIV-1 envelope glycoproteins and cellular entry receptors. We propose that MΦ infection through viral transfer from infected CD4+ T cells impacts different aspects of the pathophysiology of HIV-1 infection, renewing our understanding of the role of MΦ in HIV-1 pathogenesis and persistence.