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

Vpu from primary HIV-1 strains reduces cell-surface HLA-A, including HLA-A2, on infected cells and independently impairs TCR-mediated recognition.

• Why it matters: HIV-1 evades immune surveillance by lowering HLA class I presentation, but whether Vpu targets additional HLA molecules beyond HLA-C was unclear.
• What they did: The study tested Vpu from primary strains in infected-cell and co-culture systems, measuring HLA-A/HLA-A2 surface levels, TCR signaling, and HLA-A2-restricted CTL responses, and used coimmunoprecipitation/immunofluorescence to map Vpu–HLA-A2 interactions.
• The result: TCR signaling reduction depended on BST2/tetherin, and HLA-A2-restricted HIV-specific CTL responses were lowest when both Nef and Vpu were present; Vpu redirected HLA-A2 to a perinuclear compartment likely the trans-Golgi network via the Vpu N-terminus/transmembrane domain.

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