The retroviral Env-mediated fusion is controlled at multiple steps to prevent premature activation [2, 4] . First, the cleavage of retroviral Env precursor into SU and TM is a pre-requisite for fusion as it liberates the fusion peptide located at the amino terminus of TM so that it can insert into the target membrane upon triggering [3] . Second, post-translational modifications, such as glycosylation, are also critical for proper folding and receptor binding of Env thereby influencing membrane fusion and cell entry [5, 6, 7] . In addition, several retroviruses, such as murine leukemia virus (MLV), Mason-Pfizer monkey virus (M-PMV), equine infectious anemia virus (EIAV), etc, contain a ,16 aminoacid stretch in the CT of Env, known as R peptide, that intrinsically restricts membrane fusion [8, 9, 10] . In the latter case, the Env proteins containing the full length CT are not fusogenic in the virus-producer cells, but become fully fusogenic after viral protease cleavage of the R peptide upon budding from host cells [9, 11, 12] . The mechanism underlying the R peptide-mediated control of retroviral Env fusion is still not known. Whereas fusion of most retroviruses is triggered by receptor binding, increasing numbers of retroviruses have been shown to require a low pH, or receptor binding plus low pH, for membrane fusion [13, 14, 15, 16, 17, 18, 19, 20] . It is interesting that infection by ecotropic murine leukemia virus (E-MLV) has been shown to be blocked by inhibitors of cellular cathepsins [21] , suggesting host proteases are involved in the fusion activation of E-MLV and perhaps of other retroviruses. Similar mechanisms have been reported for other enveloped viruses [22, 23, 24, 25, 26] .