Immune evasion genes help human cytomegalovirus (HCMV) establish lifelong persistence. Without immune pressure, laboratory-adapted HCMV strains have undergone genetic alterations. Among these, the deletion of the U L/ b’ domain is associated with loss of virulence. In a screen of U L/ b’, we identified pUL135 as a protein responsible for the characteristic cytopathic effect of clinical HCMV strains that also protected from natural killer (NK) and T cell attack. pUL135 interacted directly with abl interactor 1 (ABI1) and ABI2 to recruit the WAVE2 regulatory complex to the plasma membrane, remodel the actin cytoskeleton and dramatically reduce the efficiency of immune synapse (IS) formation. An intimate association between F-actin filaments in target cells and the IS was dispelled by pUL135 expression. Thus, F-actin in target cells plays a critical role in synaptogenesis, and this can be exploited by pathogens to protect against cytotoxic immune effector cells. An independent interaction between pUL135 and talin disrupted cell contacts with the extracellular matrix.
HCMV UL135 functions during productive infection in order to evade NK and T cells
UL135 promotes actin depolymerization and suppresses cytoskeletal remodelling
UL135 interacts with ABI1 and ABI2 to relocalize the actin regulatory WAVE2 complex
ABI1/2 binding impairs immunological synapse formation to inhibit NK and T cell killing
Viruses like human cytomegalovirus (HCMV) must evade immune responses in order to establish persistent infection. Stanton et al. identify an HCMV immune evasion strategy whereby the viral protein UL135 modifies the actin cytoskeleton in the infected cell in order to prevent immune cells from forming an immune synapse, thus subverting NK and T cell killing.