Review articleFunctional roles of HIV-1 Vpu and CD74: Details and implications of the Vpu–CD74 interaction
Introduction
HIV-1 has several accessory genes, namely vif, vpr, nef and vpu. The accessory proteins encoded by these genes play important roles in viral replication [1]. Vif targets the host restriction factor APOBEC3G for proteasomal degradation to prevent the inhibition of viral DNA synthesis [2], [3], [4]. Vpr has many functions including activation of cell death and proviral transcription [4], [5]. Nef is a functionally diverse protein that is involved in the alteration of cell signaling pathways, disruption of antigen presentation by MHCI and MHCII and alteration of gene and receptor surface expression [4], [6]. Lastly, Vpu also has multiple functions within the host cell, some of which are similar to Nef, with the most well-described functions being the degradation of the HIV-1 receptor CD4 and virion release [4], [7], [8].
Of particular interest, Vpu is only encoded by the genome of HIV-1 and a few simian immunodeficiency virus (SIV) isolates such as SIVcpz (chimpanzee), SIVmon (mona monkey), SIVgsn (greater spot-nosed monkey), SIVmus (mustached monkey) and SIVden (Dent’s mona monkey), but is not found within HIV-2 [9]. Related isolates that do not express a functional Vpu protein have far less severity in terms of disease outcome [10] indicating the importance of this viral protein. HIV-1 infections tend to result in chronic immune activation, while HIV-2 infections yield lower levels of immune activation [11] and SIVs of sooty mangabeys and African green monkeys, which do not encode vpu, generally also do not cause high levels of immune activation [12]. Furthermore, the functionality of the Vpu protein in the HIV-1 strains of M, N and O has been suggested to be necessary for the spread of the pandemic M strain as this strain expresses a Vpu protein that is not only able to target CD4 for degradation, but also effectively antagonizes tetherin [4], [9]. The non-pandemic N and O strains express a Vpu protein that is lacking in one of the primary functions. Although HIV-2 targets tetherin using the Env protein, this has been found to be less effective than that of HIV-1 Vpu [9]. HIV-1 Vpu appears to target the immune system in many different but related ways that are highly effective at sabotaging the immune response and that work in conjunction with other HIV-1 proteins to more effectively enhance viral replication. As each component of the immune system that is targeted by Vpu is important, the impairment of Vpu function would likely increase the ability of the immune system to respond to HIV-1 infection.
One of the more recently described functions of Vpu is the downregulation of the MHCII, specifically through the interaction with the MHCII-associated invariant chain, or CD74 [13]. As CD74 plays a role in many important cellular functions, including the immune response, it is feasible that the binding of Vpu to this host protein has multiple downstream consequences for the immune response apart from the downregulation of the MHCII. Therefore downregulation of this host protein is beneficial for viral persistence. In this review, we take a look at the multiple functions of both Vpu and CD74 within the infected cell and examine the specific interaction and binding site between these two proteins and consider the possible ramifications of this interaction. Finally, we contemplate on the suitability of this protein–protein interaction as a possible novel therapeutic target for drug intervention.
Section snippets
HIV-1 Vpu structure
Vpu is an 81-mer type I integral intracellular membrane protein that is expressed in the later stages of viral infection. Vpu has an N-terminal transmembrane hydrophobic helix (residues 1–27) and two amphipathic helices (residues 35–50 and 58–70) that form part of the cytoplasmic domain and are separated by a linker region (residues 47–58) [14], [15], [16]. The linker region has two highly conserved serine residues in the cytoplasmic domain, namely Ser52 and Ser56 [16] that are required for the
HIV-1 Vpu functions
The two primary functions of Vpu are the degradation of CD4, the primary receptor protein for HIV-1 [23], [24], [25] and the release of new virus particles from infected cells either by inhibition of the host restriction factor, tetherin [26], [27], [28], [29] or through the viroporin activity of Vpu in which the transmembrane domain is able to form an ion channel in a separate mechanism to that of the antagonism of tetherin [30], [31], [32]. Vpu also seems to undermine or impair the immune
Human CD74 structure
CD74 consists of a 30-mer N-terminal cytoplasmic domain, a 26-mer transmembrane domain and a 160 amino acid sequence that is either extracellular or projects into the lumen, depending on the subcellular location of the protein [13]. There are several isoforms of CD74, namely p33, p35, p41 and p43 [61]. Ii-p33 and Ii-p35 are 33 kDa and 35 kDa, respectively and are involved in MHCII antigen presentation with the Ii-p33 isoform being the prominent of the two. These isoforms originate in two ways,
Human CD74 functions
One of the most well described functions of CD74 is its role in antigen presentation through association with the MHCII complex [53], [55], [56]. However, the expression of CD74 is separate to that of the MHCII molecules and this allows CD74 to have numerous other functions within the cells. During cleavage of CD74 within the endosome, a portion of the CD74-ICD translocates to the cell nucleus (Fig. 1A) and thereby initiates a signal cascade by activating the phosphatidylinositol 3′-kinase, Syk
Interaction between Vpu and CD74
Vpu and CD74 were found to interact via their cytoplasmic domains within the ER [13], similar to that of the Vpu–CD4 interaction [7]. Specific sequences in the cytoplasmic domain of Vpu were identified to be necessary to induce the degradation of CD4 [24], [84]. The CD4 binding site on Vpu overlaps with the immunodominant domain, as CD4 prevents the binding of antibodies directed against the Vpu cytoplasmic domain [7], [85]. In a similar study, it was also shown that an antibody directed
Targeting of the Vpu/CD74 interaction
Vpu is able to connect viral and host cellular proteins to cellular pathways, as well as regulate these pathways through protein–protein interactions in order to promote viral replication [23], making this protein actively involved in the establishment of infective persistence within the host. As previously mentioned, HIV or SIV isolates that do not express a functional Vpu protein have less severity in terms of disease outcome [10]. Therefore targeting the interactions of this particular
Conclusions
As both HIV-1 Vpu and the host protein CD74 have a wide variety of functions, inhibition of the interaction between these two proteins may be highly disadvantageous for viral persistence. While this interaction is easily assayable and monitored in vitro, the lack of a three dimensional structure for CD74 may delay the rational design of novel inhibitors for the specific binding site between CD74 and Vpu. Despite this the Vpu–CD74 interaction is still a viable drug target as Vpu targets
Funding source contributions
The above mentioned funding sources had no involvement in the research and preparation of this article.
Author contributions
D.L. – conceptual idea as well as writing of the review.
R.H. – conceptual idea, critical revision and final approval of submitted manuscript.
S.M. – conceptual idea, critical revision and final approval of submitted manuscript.
M.P. – conceptual idea, critical revision and final approval of submitted manuscript.
Acknowledgments
The authors wish to acknowledge Mintek and the University of the Witwatersrand for funding this research as well as the National Research Foundation for awarding the Professional Development Programme grant to the first author to conduct the research. The authors also wish to acknowledge Martine Whitehead for her expertise in the graphical design of the schematics.
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Present address: School of Biochemistry, Genetics and Microbiology, University of Kwa-Zulu Natal, Private Bag X01, Scottsville 3209, South Africa.