Retroviral Env glycoproteins are synthesized from a spliced form of the viral genomic RNA as reviewed in [23] [24] [25] (Figure 1 ). Translation of the Env protein occurs on ribosomes bound to the endoplasmic reticulum (ER) and starts with the leader sequence, which contains a small, N-terminal hydrophobic signal peptide. The Env protein is cotranslationally inserted into the lumen of the rough ER. In the ER, the leader sequence is removed by cellular signal peptidases. In addition, Env polypeptides are N-and O-glycosylated and subsequently trimmed [26, 27] . The number and location of glycosylated residues varies broadly among retroviruses. The hydrophobic transmembrane (TM) domain prevents Env proteins from being fully released into the lumen of the ER [28, 29]. The amino acid sequence following the TM is referred to as the cytoplasmic tail (CT), which varies from 30 to around 150 residues, depending on the virus. Env proteins are folded and assembled into oligomers in the RER. Retroviral Env proteins form trimers [30] [31] [32] [33] . The HIV-1 accessory protein Vpu binds to the CD4 receptor through its cytoplasmic domain and downregulates the receptor by transporting it to the proteasome for degradation, thereby preventing premature interactions between Env and its receptor [34] [35] [36] .