Human metapneumovirus (HMPV) is a leading cause of respiratory
infection that causes upper airway and severe lower
respiratory tract infections. HMPV
infection is initiated by viral
surface glycoproteins that attach to cellular receptors and mediate virus membrane fusion with cellular membranes. Most paramyxoviruses use two viral
glycoproteins to facilitate virus entry-an attachment
protein and a fusion (F)
protein. However, membrane fusion for the human paramyxoviruses in the Pneumovirus subfamily, HMPV and respiratory syncytial virus (hRSV), is unique in that the F
protein drives fusion in the absence of a separate viral attachment
protein. Thus, pneumovirus F
proteins can perform the necessary functions for virus entry, i.e., attachment and fusion. In this review, we discuss recent advances in the understanding of how HMPV F mediates both attachment and fusion. We review the requirements for HMPV viral
surface glycoproteins during entry and
infection, and review the identification of cellular receptors for HMPV F. We also review our current understanding of how HMPV F mediates fusion, concentrating on structural regions of the
protein that appear to be critical for membrane fusion activity. Finally, we illuminate key unanswered questions and suggest how further studies can elucidate how this clinically important
paramyxovirus fusion protein may have evolved to initiate
infection by a unique mechanism.