Relevance of the Entry by Fusion at the Cytoplasmic Membrane vs. Fusion After Endocytosis in the HIV and SARS-Cov-2 Infections.

HIV-1 and SARS-Cov-2 fuse at the cell surface or at endosomal compartments for entry into target cells; entry at the cell surface associates to productive infection, whereas endocytosis of low pH-independent viruses may lead to virus inactivation, slow replication, or alternatively, to productive infection. Endocytosis and fusion at the cell surface are conditioned by cell type-specific restriction factors and the presence of enzymes required for activation of the viral fusogen. Whereas fusion with the plasma membrane is considered the main pathway to productive infection of low pH-independent entry viruses, endocytosis is also productive and may be the main route of the highly efficient cell-to-cell dissemination of viruses. Alternative receptors, membrane cofactors, and the presence of enzymes processing the fusion protein at the cell membrane, determine the balance between fusion and endocytosis in specific target cells. Characterization of the mode of entry in particular cell culture conditions is desirable to better assess the effect of neutralizing and blocking agents and their mechanism of action. Whatever the pathway of virus internalization, production of the viral proteins into the cells can lead to the expression of the viral fusion protein on the cell surface; if this protein is able to induce membrane fusion at physiological pH, it promotes the fusion of the infected cell with surrounding uninfected cells, leading to the formation of syncytia or heterokaryons. Importantly, particular membrane proteins and lipids act as cofactors to support fusion. Virus-induced cell-cell fusion leads to efficient virus replication into fused cells, cell death, inflammation, and severe disease.