Avian leukosis virus (ALV) has been used as a model system to understand th
e mechanism of pH-independent viral entry involving receptor-induced confor
mational changes in the viral envelope (Env) glycoprotein that lead to memb
rane fusion. Here, we report the unexpected finding that ALV entry depends
on a critical low pH step that was overlooked when this virus was directly
compared to the classical pH-dependent influenza A virus. In contrast to in
fluenza A virus, receptor interaction plays an essential role in priming AL
V Env for subsequent low pH triggering. Our results reveal a novel principl
e in viral entry, namely that receptor interaction can convert a pH-insensi
tive viral glycoprotein to a form that is responsive to low pH.