HIV-1 Spread Between Macrophages Sidesteps the BST-2 Tetherin Restriction Factor

HIV-1 can spread from infected T cells to macrophages through direct cell-to-cell transfer, a route in which the cells fuse and form virus-productive multinucleated giant cells (MGCs). New research from Sen Yan, Agathe Durringer, Marie Woottum and Serge Benichou, published in PLOS Pathogens, reports that this mode of infection also bypasses host restriction factors acting on the late steps of the viral life cycle, not just those acting on early steps.

The team focused on BST-2, also known as tetherin, an interferon-induced host factor that restrains the release of newly formed viral particles from the cell surface. HIV-1 normally counteracts BST-2 with its Vpu protein. In experiments with interferon-stimulated macrophages, the researchers found that deleting Vpu did not significantly affect HIV-1 cell-to-cell infection. Virus assembly within the virus-containing compartments of MGCs was likewise unaffected.

Consistent with these observations, depleting BST-2 in interferon-stimulated macrophages had no impact on cell-to-cell virus transfer, the formation of MGCs, or virus production. The authors conclude that this route of macrophage infection escapes BST-2-mediated restriction independently of the Vpu counteracting protein.

The study builds on the group’s earlier finding that cell-to-cell infection of macrophages escapes host factors restricting the early steps of the viral life cycle. Taken together, the results indicate that HIV-1 cell-to-cell infection of macrophages evades restriction factors acting on both early and late stages of replication.

However, the route is not entirely drug-resistant. Cell-to-cell infection of macrophages remained sensitive to the protease inhibitor nelfinavir, whereas the authors’ previous work showed that this infection route resists antiviral drugs acting on early steps of virus replication. The findings therefore characterize a specific vulnerability profile: resistance to drugs targeting early replication steps, but sensitivity to at least one protease inhibitor, alongside broad escape from host cell restriction factors.

Subject of Research: Escape of HIV-1 cell-to-cell infection of macrophages from the BST-2 restriction factor and its dependence on antiviral drug sensitivity

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

Article References: Yan, S., Durringer, A., Woottum, M., & Benichou, S. (2026). HIV-1 cell-to-cell infection of macrophages escapes restriction by the BST-2 host cell factor independently of the Vpu counteracting viral protein. PLOS Pathogens, 22(10), e1014702. https://doi.org/10.1371/journal.ppat.1014702

Image Credits: AI Generated

DOI: 10.1371/journal.ppat.1014702

Keywords: HIV-1, macrophages, BST-2, tetherin, Vpu, cell-to-cell transmission, multinucleated giant cells, interferon, restriction factors, nelfinavir, PLOS Pathogens, cell-to-cell