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CMV Targets the Immune Checkpoint Inhibitor BTLA

Virulent isolates of CMV encode the ul144 orf, and we identified UL144 as an orthologue of the herpesvirus entry mediator (HVEM), a member of the TNF receptor superfamily. When the immune checkpoint inhibitor B and T lymphocyte attenuator (BTLA) was identified as a ligand for HVEM, we showed that UL144 was a specific binding partner for BTLA, and not the other known HVEM ligands LIGHT, LTa and CD160. Strikingly, UL144 inhibits the activation of human T cells to a much greater degree than does HVEM, highlighting how CMV has evolved novel ways to inhibit antiviral immune responses. We have recently shown that UL144 is expressed in myeloid cells latently infected with HCMV, strongly suggesting that this viral protein plays a key role in promoting persistence of this virus in humans. In addition, UL144 can suppress the function of human natural killer (NK) cells by binding to BTLA. Further studies regarding the functional consequences of the UL144-BTLA interaction, both during lytic and latent infection, are a topic of current interest for our lab.