The cell biology of receptor-mediated virus entry

Grove, Joe; Marsh, Mark

Although it is clear that many viruses-in particular, pH-dependent viruses-have an absolute dependence on endocytosis for productive infection, some viruses may exhibit plasticity in their mechanism of entry. For example, a study has demonstrated entry by direct fusion at the cell surface as well as by fusion after endocytosis for herpesviruses (Heldwein and Krummenacher, 2008) . For HIV, pH-independent fusion, the ability of infected cells to form syncytia, and images of putative fusion events at the cell surface have led to the idea that entry occurs by direct fusion at the plasma membrane (Stein et al., 1987) . However, work with inhibitors of endocytosis and direct single-particle tracking have recently provided evidence that fusion and infection occur after endocytic uptake (Daecke et al., 2005; Miyauchi et al., 2009; von Kleist et al., 2011) . Moreover, HIV infection of macrophages has been suggested to require an atypical form of macropinocytosis (Maréchal et al., 2001; Carter et al., 2011) . Thus, factors that influence the kinetics of fusion and internalization, such as receptor density and mobility, may determine whether pH-independent viruses penetrate directly at the cell surface or after endocytosis. The ability to use different mechanisms may have distinct advantages for viruses, providing access to a broader range of cell types or rendering them less susceptible to situations in which a specific pathway is absent or blocked.