Antagonistic Determinants Controlling Replicative and Latent States of Human Cytomegalovirus Infection

Themechanisms by which viruses persist and particularly those by which viruses actively contribute to their own latency have been elusive. Here we report the existence of opposing functions encoded by genes within a polycistronic locus of the human cytomegalovirus (HCMV) genome that regulate cell type-dependent viral fates: replication and latency. The locus, referred to as theUL133-UL138 (UL133/8) locus, encodes four proteins, pUL133, pUL135, pUL136, and pUL138. As part of the ULb = region of the genome, theUL133/8 locus is lost upon serial passage of clinical strains of HCMV in cultured fibroblasts and is therefore con-sidered dispensable for replication in this context. Strikingly, we could not reconstitute infection in permissive fibroblasts from bacterial artificial chromosome clones of the HCMV genome whereUL135 alone was disrupted. The loss ofUL135 resulted in complex phenotypes and could ultimately be overcome by infection at high multiplicities. The requirement forUL135 but not the entire locus led us to hypothesize that another gene in this locus suppressed virus replication in the absence ofUL135. The defect associated with the loss ofUL135was largely rescued by the additional disruption of theUL138 latency determinant, indi-cating a requirement forUL135 for virus replication whenUL138 is expressed. In the CD34 hematopoietic progenitor model of latency, viruses lacking onlyUL135were defective for viral genome amplification and reactivation. Taken together, these data indicate thatUL135 andUL138 comprise a molecular switch wherebyUL135 is required to overcomeUL138-mediated suppres-sion of virus replication to balance states of latency and reactivation