Functional roles of HIV-1 Vpu and CD74: Details and implications of the Vpu–CD74 interaction

•Vpu is an important accessory protein of HIV-1 that is found in a few SIV isolates, but not in HIV-2 and has many important functions that assist in disease progression.•Virus isolates that do not contain a fully functional Vpu protein have less severity in disease outcome, highlighting the importance of this protein for HIV-1 persistence.•Human CD74 plays a role in a variety of important functions within the cell including antigen presentation through chaperoning MHCII for immune activation and cell signaling through binding MIF. CD74 is also involved in B cell proliferation and maturation.•Vpu and CD74 interact via their cytoplasmic domains within the ER resulting in the downregulation of MHCII and decrease in antigen presentation, ultimately affecting immune activation.•The Vpu–CD74 interaction is a viable drug target. Inhibition of this interaction may be advantageous to the infected host as unbound CD74 would be able to continue its important functions within the broad spectrum of the immune system. HIV-1 Vpu has a variety of functions, including CD4 degradation and the downregulation of MHCII. Downregulation of the MHCII occurs through Vpu binding to the cytoplasmic domain of CD74, the chaperone for antigen presentation. The CD74 cytoplasmic domain also plays a vital role in cell signaling through the activation of an NF-κB signal cascade for the maturation, proliferation and survival of B cells as well as by binding the macrophage inhibitory factor. In view of these functions, it follows that the Vpu–CD74 interaction has multiple downstream consequences for the immune system as it not only impairs foreign antigen presentation but may also have an effect on signal transduction cascades. It is thought that Vpu specifically targets intracellular CD74 while other HIV-1 proteins cannot. Therefore, this protein–protein interaction would be a potential drug target in order to reduce viral persistence. We review the functional importance and specific binding site of Vpu and CD74.