HIV-1 Vpu complements HLA-A downregulation by Nef and impairs TCR-mediated recognition of HIV-infected cells through distinct mechanisms

Many viruses, including HIV-1, target the human leukocyte antigen (HLA) class I molecules HLA-A, HLA-B, and HLA-C to evade immune surveillance. HIV-1 Nef selectively downregulates HLA-A and HLA-B, whereas Vpu variants from primary strains reduce cell-surface HLA-C expression. Whether HIV-1 also uses Vpu to target other HLA molecules has remained unclear. Here, we show that Vpu from primary strains reduces HLA-A, including the globally prevalent HLA-A2, on infected cells. Although Nef is the principal modulator of these molecules, Vpu acts independently of Nef and impairs TCR-mediated recognition of infected cells in co-culture systems. However, the reduction in TCR signaling is also dependent on the presence of BST2/tetherin, a restriction factor that retains nascent virions and targets them for degradation. HLA-A2-restricted, HIV-specific CTL responses were lowest when both Nef and Vpu were present. Vpu variants from chronic and transmitted/founder strains, but not from the prototypical recombinant strain NL4.3, were sufficient to reduce cell-surface HLA-A2, although activity varied widely among variants and appears to have arisen independently in different hosts. Coimmunoprecipitation and immunofluorescence analyses showed that Vpu interacts with HLA-A2 and redirects it to a perinuclear compartment which is probably the trans-Golgi network through a mechanism governed by the Vpu N-terminus/transmembrane domain. Overall, our findings reveal a previously unrecognized function of Vpu and show how HIV-1 uses Nef and Vpu to limit HLA-A-mediated viral antigen presentation and promote immune evasion.

Bego, M. G., Pham, T. N., Champagne, C., Sharma, V., Laporte, M., Dallaire, F., Martin, W., Brockman, M. A., Kirchhoff, F., Cohen, E. A.

Stats

Post a comment

You need to be signed in to post comments. You can sign in here.

Comments

There are no comments yet.