Understanding how HIV-1 hijacks the functions of immune cells to promote viral spreading remains a challenge in the fight against infection. Macrophages are ubiquitous tissue-resident cells, involved in tissue homeostasis and immunity. In HIV-1 infection, along with CD4+ T lymphocytes, macrophages 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 macrophages 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 macrophages. We hypothesized that these assays, which evaluate infection using cell-free viruses, might not fully reflect the modes of macrophage 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 macrophages, 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, CD4 and the chemokine receptors CCR5 and CXCR4. These results indicate that HIV-1 strains have a more prevalent tropism for macrophages than initially suggested. This sheds light into the role of this route of virus cell-to-cell transfer to macrophages in CD4+ T cell rich tissues for HIV-1 transmission, dissemination and formation of tissue viral reservoirs.
We propose that macrophage 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 macrophage in HIV-1 pathogenesis and persistence.
Reference
Han M, Cantaloube-Ferrieu V, Xie M, Armani-Tourret M, Woottum M, Pagès J-C, et al. (2022) HIV-1 cell-to-cell spread overcomes the virus entry block of non-macrophage-tropic strains in macrophages. PLoS Pathog 18(5): e1010335. https://doi.org/10.1371/journal.ppat.1010335
