Measles Fusion Machinery Is Dysregulated in Neuropathogenic Variants

E.M.J. and C.M. contributed equally to this work. ABSTRACT Paramyxoviruses, including the human pathogenmeasles virus (MV), enter host cells by fusing their viral envelope with the target cell membrane. This fusion process is driven by the concerted actions of the two viral envelope glycoproteins, the receptor binding protein (hemagglutinin [H]) and the fusion (F) protein. H attaches to specific proteinaceous receptors on host cells; once the receptor engages, H activates F to directly mediate lipid bilayer fusion during entry. In a recent MV outbreak in South Africa, several HIV-positive people died of MV central nervous system (CNS) infection. We analyzed the virus sequences from these patients and found that specific intrahost evolution of the F protein had occurred and resulted in viruses that are “CNS adapted. ” Amutation in F of the CNS-adapted virus (a leucine-to-tryptophan change present at position 454) allows it to promote fusion with less dependence on engagement of H by the two known wild-type (wt) MV cellular receptors. This F protein is activated independently of H or the receptor and has reduced thermal stability and increased fusion activity compared to those of the corresponding wt F. These functional effects are the result of the single L454Wmutation in F.We hypothesize that in the absence of effective cellular immunity, such as HIV infection, MV variants bearing altered fusionmachinery that enabled effi-cient spread in the CNS underwent positive selection. IMPORTANCE Measles virus has become a concern in the United States and Europe due to recent outbreaks and continues to be