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

• DOI: 10.1371/journal.ppat.1010335
• Publication Date: 2022-05-27T17:39:55Z
• Authors: Mingyu Han; Vincent Cantaloub...; Maorong Xie; Marie Armani-Tourret; Marie Woottum; Jean-Christophe P...; Philippe Colin; Bernard Lagane; Serge Benichou
• Keywords: CD4-Positive T-Lymphocytes; 0301 basic medicine; Bone marrow cells; Receptors, CCR5; QH301-705.5; T cells; HIV Infections; 03 medical and health sciences; Humans; Biology (General); Cell fusion; Viral tropism; 0303 health sciences; Macrophages; RC581-607; Virus Internalization; Cell staining; 3. Good health; [SDV] Life Sciences [q-bio]; CD4 Antigens; 293T cells; HIV-1; Immunologic diseases. Allergy; Research Article

Macrophages (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.