Abstract
Productive herpesvirus infection requires a profound, time-controlled remodeling of the viral transcriptome and proteome. To gain insights into the genomic architecture and gene expression control in Kaposi's sarcoma-associated herpesvirus (KSHV), we performed a systematic genome-wide survey of viral transcriptional and translational activity throughout the lytic cycle. Using mRNA-sequencing and ribosome profiling, we found that transcripts encoding lytic genes are promptly bound by ribosomes upon lytic reactivation, suggesting their regulation is mainly transcriptional. Our approach also uncovered new genomic features such as ribosome occupancy of viral non-coding RNAs, numerous upstream and small open reading frames (ORFs), and unusual strategies to expand the virus coding repertoire that include alternative splicing, dynamic viral mRNA editing, and the use of alternative translation initiation codons. Furthermore, we provide a refined and expanded annotation of transcription start sites, polyadenylation sites, splice junctions, and initiation/termination codons of known and new viral features in the KSHV genomic space which we have termed KSHV 2.0. Our results represent a comprehensive genome-scale image of gene regulation during lytic KSHV infection that substantially expands our understanding of the genomic architecture and coding capacity of the virus.
Highlights
Kaposi’s sarcoma-associated herpesvirus (KSHV) is a member of the gamma-herpesvirus family and the etiologic agent of Kaposi’s sarcoma, primary effusion lymphoma (PEL), and multicentric Castleman’s disease [1,2]
We found that the viral genome has a large coding capacity, capable of generating at least 45% more products than initially anticipated by bioinformatic analyses alone, and that it uses multiple strategies to expand its coding capacity well beyond what is determined solely by the DNA sequence of its genome
We provide an expanded and highly detailed annotation of known and new genomic features in KSHV
Summary
Kaposi’s sarcoma-associated herpesvirus (KSHV) is a member of the gamma-herpesvirus family and the etiologic agent of Kaposi’s sarcoma, primary effusion lymphoma (PEL), and multicentric Castleman’s disease [1,2]. The KSHV genome, a dsDNA molecule of ,165 kb, was sequenced from the lymphoid cell line BC-1, allowing the in silico annotation of open reading frames (ORFs) that fit the following criteria: (1) they start with a canonical initiator AUG codon and (2) they encode polypeptides larger than 100 amino acids (aa). Many of these ORFs had functional homologues in herpesvirus saimiri (HVS), a gamma-herpesvirus related to KSHV [4]. In spite of all the aforementioned efforts, a detailed understanding of the genomic architecture, translational state, and biological functions of KSHV gene products remains incomplete
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