Human cytomegalovirus lytic infection inhibits replication-dependent histone synthesis and requires stem loop binding protein function.

Replication-dependent (RD) histones are deposited onto human cytomegalovirus (HCMV) genomes at the start of infection. We examined how HCMV affects the de novo production of RD histones and found that viral infection blocked the accumulation of RD histone mRNAs that normally occurs during the S phase. Furthermore, RD histone mRNAs present in HCMV-infected cells did not undergo the unique 3′ processing required for their normal nuclear export and translation. The protein that orchestrates processing in the nucleus, stem loop–binding protein (SLBP), was found predominantly in the cytoplasm, and RD histone proteins were not de novo synthesized in HCMV-infected cells. Intriguingly, however, we found that SLBP was required for the efficient synthesis and assembly of infectious progeny virions. We conclude that HCMV infection attenuates RD histone mRNA accumulation and processing and the de novo protein synthesis of the RD histones, while utilizing SLBP for an alternative purpose to support infectious virion production.