Activation of membrane fusion by murine leukemia viruses is controlled in cis or in trans by interactions between the receptor-binding domain and a conserved disulfide loop of the carboxy terminus of the surface glycoprotein

Cell entry of retroviruses is initiated by the recognition of cellular rece ptors and the subsequent membrane fusion between viral and cellular membran es, These two steps are mediated by the surface (SU) and transmembrane (TM) subunits of the retroviral envelope glycoprotein (Env), respectively. Dete rminants regulating membrane fusion have been described throughout SU and T M, but the processes coupling receptor recognition to fusion are still elus ive. Here we establish that a critical interaction is formed between the re ceptor-binding domain (RBD) and the major disulfide loop of the carboxy-ter minal domain (C domain) of the murine leukemia virus SU, Receptor binding c auses an alteration of this interaction and, in turn, promotes further even ts of Env fusion activation, We characterize mutations which, by lowering t his interaction and reducing the compatibility between the RBD and C domain s of Env glycoprotein chimeras, affect both Env fusogenicity and sensitivit y to receptor interference, Additionally, we demonstrate that suboptimal in teractions in such mutant Env proteins can be compensated in trans by solub le RBDs in a manner that depends on their compatibility with the C domain. Our results therefore indicate that RBD/C domain interactions may occur in cis, via the proper RBD of the viral Env itself, or in trans, via a distinc t RBD expressed by virion-free Env glycoproteins expressed endogenously by the infected cells or provided by neighboring Env trimers.