Abstract:

HIV-1 remains a major global health issue despite the considerable success of combined antiretroviral therapy in controlling viral replication. One of the main obstacles to viral eradication is the persistence of long-lived viral reservoirs in tissues of people living with HIV. Among HIV-1 target cells, macrophages are thought to contribute to viral dissemination, persistence, and reservoir establishment. Although macrophages are relatively resistant to cell-free infection because of the strong expression of host restriction factors, HIV-1 can be efficiently transmitted to these cells by cell-to-cell transfer from infected CD4 T cells. In particular, fusion between infected T cells and macrophages leads to the formation of highly virus-producing multinucleated giant cells, which are frequently observed in infected tissues.

This thesis shows that HIV-1 cell-to-cell transfer to macrophages by cell-cell fusion bypasses several antiviral mechanisms that normally restrict infection. Viral auxiliary proteins such as Vif, Vpr, Nef and Vpu, which are important for overcoming host restriction factors during cell-free infection, are not required for this route of infection. In addition, type I interferon stimulation does not efficiently block macrophage infection by cell-cell fusion. In agreement with these observations, depletion of the restriction factors SERINC5, APOBEC3G and BST-2/tetherin does not significantly alter viral spread, formation of multinucleated giant cells, or virus production in macrophages.

To better understand the potential mechanisms involved, the distinct nuclei present in multinucleated giant cells were further investigated. The results show that nuclei derived from infected T cells remain transcriptionally active after fusion with macrophage targets, likely supporting ongoing viral replication in these hybrid cells. In parallel, viral DNA was unexpectedly detected in myeloid nuclei shortly after fusion, suggesting that viral material can rapidly access macrophage nuclei during this process. Finally, while this mode of infection is resistant to antiretroviral drugs targeting early steps of replication, it remains sensitive to the protease inhibitor nelfinavir, revealing a selective vulnerability at the level of viral maturation. Together, these findings show that HIV-1 infection of macrophages by cell-cell fusion is a highly efficient pathway that bypasses both innate antiviral restriction and part of antiretroviral treatments, and may therefore contribute to the persistence of macrophage viral reservoirs.