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 UL/b' domain is associated with loss of virulence. In a screen of UL/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.

Institute of Cancer and Genetics Cardiff University School of Medicine Heath Park Cardiff CF14 4XN UK

Institute of Infection and Immunity Cardiff University School of Medicine Heath Park Cardiff CF14 4XN UK

Ludwig Maximilians Universität München Max von Pettenkofer Institut Pettenkoferstrasse 9a 80336 München Germany

Ludwig Maximilians Universität München Max von Pettenkofer Institut Pettenkoferstrasse 9a 80336 München Germany; Biological Interfacial Engineering University of Stuttgart Nobelstrasse 12 70569 Stuttgart Germany

Medical Research Council University of Glasgow Centre for Virus Research Glasgow G11 5JR UK

Regional Centre for Applied Molecular Oncology Masaryk Memorial Cancer Institute 65653 Brno Czech Republic

Section of Hepatology Department of Medicine Imperial College London London W2 1PG UK

University of Cambridge Cambridge Institute for Medical Research Addenbrooke's Hospital Hills Road Cambridge CB2 0XY UK

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Suppression of costimulation by human cytomegalovirus promotes evasion of cellular immune defenses

Plasma membrane profiling defines an expanded class of cell surface proteins selectively targeted for degradation by HCMV US2 in cooperation with UL141