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

PLoS Pathog. 2022 May 27;18(5):e1010335. doi: 10.1371/journal.ppat.1010335. eCollection 2022 May.

Abstract

Macrophages (MΦ) are increasingly recognized as HIV-1 target cells involved in the pathogenesis and persistence of infection. Paradoxically, in vitro infection 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 of in vivo MΦ 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • CD4 Antigens / metabolism
  • CD4-Positive T-Lymphocytes
  • HIV Infections* / metabolism
  • HIV-1* / metabolism
  • Humans
  • Macrophages / metabolism
  • Receptors, CCR5 / metabolism
  • Virus Internalization

Substances

  • CD4 Antigens
  • Receptors, CCR5

Grants and funding

This work was supported in part by Inserm, CNRS, and the University Paris-Descartes. It was also funded by grants from the Agence Nationale de Recherche sur le SIDA et les Hépatites Virales (ANRS). M.H. and M.X. were supported by grants from the China Scholarship Council (CSC). V.C.-F. and M.W. were supported by a grant from ANRS. M.A.-T was funded by a grant from Sidaction. The funders play any role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.