CD6 downregulation from cell surface in human herpesvirus-6A/B-infected T cells

Human herpesvirus 6A/B (HHV-6A/B) belongs to the Betaherpesvirinae subfamily and mainly replicates in activated T cells. Although HHV-6B establishes lifelong latency after primary infection and infects nearly all adult humans, its immune evasion strategies in vivo remain incompletely understood. CD6 is a key costimulatory receptor that shapes T-cell activation and communication. Here, we identify CD6 as a previously unrecognized target of HHV-6A/B. Infection triggered internalization of CD6 from the plasma membrane into the cytoplasm and led to its proteasome-dependent degradation. CD6 transcription and maturation through the secretory pathway were unaffected, indicating that downregulation occurs through post-transcriptional mechanisms involving altered endolysosomal trafficking. We further demonstrate that the virus-specific U21-U24 gene cluster is required for CD6 downregulation, as deletion of this cluster abolished CD6 degradation in both T-cell lines and primary cord blood mononuclear cells. These findings reveal a viral strategy that disrupts T-cell surface architecture and suggest a role for CD6 modulation in supporting HHV-6A/B persistence.IMPORTANCEHuman herpesvirus 6B (HHV-6B) infects nearly all individuals early in life and persists lifelong, yet the mechanisms by which it modulates host immunity remain poorly defined. CD6 is a critical costimulatory receptor that shapes T-cell activation and communication within the immune system. Here, we identify CD6 as a previously unrecognized target of HHV-6A/B and demonstrate that infection triggers its internalization and proteasome-dependent degradation. We further show that this process is driven by the virus-specific U21-U24 gene cluster, revealing a dedicated viral strategy for altering host protein trafficking. Because degradation of immune surface molecules is a common mechanism of immune evasion among persistent viruses, our findings provide new insight into how HHV-6A/B remodels T-cell function to support long-term persistence. Understanding this pathway may inform future approaches aimed at preventing or mitigating diseases associated with HHV-6 reactivation.