Membrane attachment and fusion of HIV-1, influenza A, and SARS-CoV-2: resolving the mechanisms with biophysical methods

Attachment to and fusion with cell membranes are two major steps in the replication cycle of many human viruses. We focus on these steps for three enveloped viruses, i.e., HIV-1, IAVs, and SARS-CoV-2. Viral spike proteins drive the membrane attachment and fusion of these viruses. Dynamic interactions between the spike proteins and membrane receptors trigger their specific attachment to the plasma membrane of host cells. A single virion on cell membranes can engage in binding with multiple receptors of the same or different types. Such dynamic and multivalent binding of these viruses result in an optimal attachment strength which in turn leads to their cellular entry and membrane fusion. The latter process is driven by conformational changes of the spike proteins which are also class I fusion proteins, providing the energetics of membrane tethering, bending, and fusion. These viruses exploit cellular and membrane factors in regulating the conformation changes and membrane processes. Herein, we describe the major structural and functional features of spike proteins of the enveloped viruses including highlights on their structural dynamics. The review delves into some of the case studies in the literature discussing the findings on multivalent binding, membrane hemifusion, and fusion of these viruses. The focus is on applications of biophysical tools with an emphasis on single-particle methods for evaluating mechanisms of these processes at the molecular and cellular levels.