Abstract
Many viruses use a pH-dependent pathway for fusion with host cell membrane, the mechanism of which is still poorly understood. Here we report that a subtle leucine (Leu)-valine (Val) change at position 501 in the envelope glycoproteins (Envs) of two related retroviruses, jaagsiekte sheep retrovirus (JSRV) and enzootic nasal tumor virus (ENTV), is responsible for their distinct low pH requirements for membrane fusion and infection. The Leu and Val residues are predicted to reside within the C-terminal heptad repeat (HR2) region of JSRV and ENTV Envs, particularly proximal to the hairpin turn of the putative six-helix bundle (6HB). Substitution of the JSRV Leu with a Val blocked the Env-mediated membrane fusion at pH 5.0, whereas replacement of the ENTV Val with a Leu rendered the ENTV Env capable of fusing at pH 5.0. A Leu-Val change has no apparent effect on the stability of native Env, but appears to stabilize an intermediate induced by receptor binding. These results are consistent with the existence of at least two metastable conformations of these viral glycoproteins, the native prefusion conformation and a receptor-induced metastable intermediate. Collectively, this work represents an interesting perhaps unique example whereby a simple Leu-Val change has critical impact on pH-dependent virus fusion and entry.
Highlights
The mechanism of viral membrane fusion is still poorly understood
The Ectodomain of TM Determines Distinct Low pH Requirements of jaagsiekte sheep retrovirus (JSRV) and enzootic nasal tumor virus (ENTV) envelope glycoproteins (Envs) for Fusion—We recently showed that the SU subunit of ENTV Env is responsible for its intrinsic low fusogenicity, whereas the TM subunit dictates the differential low pH requirements for membrane fusion between JSRV and ENTV Env [25]
To identify which domain(s) of the TM are responsible for the differential low pH requirements for fusion between JSRV and ENTV Envs, we created a series of reciprocal chimeras in the cytoplasmic tail (CT), membrane-spanning domain (MSD), and ectodomain of the TM (Fig. 1A), respectively, and characterized their fusion properties
Summary
Results: We show that a leucine-valine change in the JSRV and ENTV Env is responsible for their distinct low pH requirements for fusion. We report that a subtle leucine (Leu)-valine (Val) change at position 501 in the envelope glycoproteins (Envs) of two related retroviruses, jaagsiekte sheep retrovirus (JSRV) and enzootic nasal tumor virus (ENTV), is responsible for their distinct low pH requirements for membrane fusion and infection. A Leu-Val change has no apparent effect on the stability of native Env, but appears to stabilize an intermediate induced by receptor binding. This work represents an interesting perhaps unique example whereby a simple Leu-Val change has critical impact on pH-dependent virus fusion and entry. SU is responsible for binding to the specific cellular receptors or coreceptors, whereas TM is directly involved in fusion between virus and cell membrane
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