HIV-1 cell-to-cell infection of macrophages escapes restriction by the BST-2 host cell factor independently of the Vpu counteracting viral protein

Abstract

As HIV-1 target cells, macrophages can be infected by cell-to-cell virus transfer from infected T cells through cell-cell fusion leading to the formation of virus-productive multinucleated giant cells (MGCs). We recently demonstrated that this route of infection escaped host cell restriction acting on the early steps of the viral life cycle. Here, we investigated whether restriction factors acting on late steps of HIV-1 replication were also bypassed in virus cell-to-cell infection of macrophages. We focused on the impact of the interferon(IFN)-induced factor BST-2/tetherin acting on virus release, a process counteracted by the Vpu viral protein. We show that deletion of Vpu did not significantly affect HIV-1 cell-to-cell infection of IFN-stimulated macrophages, and virus assembly in virus containing compartments was not affected in MGCs. Accordingly, depletion of BST-2 in IFN-stimulated macrophages had no impact on virus cell-to-cell transfer, formation of MGCs and virus production. However, cell-to-cell infection of macrophages was still sensitive to the nelfinavir protease inhibitor, whereas we previously showed that this route of infection was resistant to antiviral drugs acting on early steps of virus replication. Our results show that HIV-1 cell-to-cell infection of macrophages escapes restriction factors acting on both early and late steps of the virus life cycle, but displays resistance to antiviral drugs specifically acting on the early steps of virus replication.

The authors' abstract, as published at the source. PLoS Pathogens, 2026 · DOI ↗