HIV-1 cell-to-cell spread overcomes the virus entry block of non-macrophage-tropic strains in macrophages
Authors: Han Mingyu , Cantaloube-Ferrieu Vincent , Xie Maorong , Armani-Tourret Marie , Woottum Marie , Pagès Jean-Christophe , Colin Philippe , Lagane Bernard , Benichou Serge 
Published: February 2022

AbstractMacrophages (MΦ) are increasingly recognized as HIV-1 target cells involved in the pathogenesis and persistence of infection. Paradoxically,in vitroinfection assays suggest that virus isolates are mostly T-cell-tropic and rarely MΦ-tropic. The latter are assumed to emerge under CD4+ T-cell paucity in tissues such as the brain or at late stage when the CD4 T-cell count declines. However, assays to qualify HIV-1 tropism use cell-free viral particles and may not fully reflect the conditions ofin vivoMΦ infection through cell-to-cell viral transfer. Here, we investigated the capacity of viruses expressing primary envelope glycoproteins (Envs) with CCR5 and/or CXCR4 usage from different stages of infection, including transmitted/founder Envs, to infect MΦ by a cell-free mode and through cell-to-cell transfer from infected CD4+ T cells. The results show that most viruses were unable to enter MΦ as cell-free particles, in agreement with the current view that non-M-tropic viruses inefficiently use CD4 and/or CCR5 or CXCR4 entry receptors on MΦ. In contrast, all viruses could be effectively cell-to-cell transferred to MΦ from infected CD4+ T cells. We further showed that viral transfer proceeded through Env-dependent cell-cell fusion of infected T cells with MΦ targets, leading to the formation of productively infected multinucleated giant cells. Compared to cell-free infection, infected T-cell/MΦ contacts showed enhanced interactions of R5 M- and non-M-tropic Envs with CD4 and CCR5, resulting in a reduced dependence on receptor expression levels on MΦ for viral entry. Altogether, our results show that virus cell-to-cell transfer overcomes the entry block of isolates initially defined as non-macrophage-tropic, indicating that HIV-1 has a more prevalent tropism for MΦ than initially suggested. This sheds light into the role of this route of virus cell-to-cell transfer to MΦ in CD4+ T cell rich tissues for HIV-1 transmission, dissemination and formation of tissue viral reservoirs.Author SummaryUnderstanding 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 whereasin vitrocellular 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.