Abstract
Lytic infection by Kaposi's sarcoma-associated herpesvirus (KSHV) is associated with an extensive shutoff of host gene expression, mediated chiefly by accelerated mRNA turnover due to expression of the viral SOX protein. We have previously identified a small number of host mRNAs that can escape SOX-mediated degradation. Here we present a detailed, transcriptome-wide analysis of host shutoff, with careful microarray normalization to allow rigorous determination of the magnitude and extent of transcript loss. We find that the extent of transcript reduction represents a continuum of susceptibilities of transcripts to virus-mediated shutoff. Our results affirm that the levels of over 75% of host transcripts are substantially reduced during lytic infection, but also show that another ∼20% of cellular mRNAs declines only slightly (less than 2-fold) during the course of infection. Approximately 2% of examined cellular genes are strongly upregulated during lytic infection, most likely due to transcriptional induction of mRNAs that display intrinsic SOX-resistance.
Highlights
Kaposi’s sarcoma-associated herpesvirus (KSHV) is a lymphotropic herpesvirus that is etiologically linked to Kaposi’s sarcoma (KS) as well as to several lymphoproliferative syndromes [1,2,3,4,5]
Many different cell types comprise the hallmark angioproliferative lesions in KS; only the spindle cells, which are of endothelial origin, are infected with KSHV [33,34,35]
Dissecting the relative contributions of each of these factors to the overall pattern of host mRNA accumulation will likely require genetic and functional genomic analyses of each coding region, carried out in the context of lytic KSHV replication. These studies represent a comprehensive examination of the host endothelial transcriptome during lytic infection by KSHV, using methods that allow quantitative assessment of the magnitude and scope of mRNA abundance changes as infection progresses
Summary
Kaposi’s sarcoma-associated herpesvirus (KSHV) is a lymphotropic (gamma-2) herpesvirus that is etiologically linked to Kaposi’s sarcoma (KS) as well as to several lymphoproliferative syndromes [1,2,3,4,5]. Latently infected cells retain the full viral genome and, under the appropriate conditions, can be induced to enter the lytic cycle [11,12] In this state, the majority of viral genes are expressed according to a temporally regulated program, with immediateearly (IE) genes expressed first, followed by delayed-early (DE) genes [13]. Of the 169 probes analyzed, only 14% were uniquely induced by vGPCR expression; fully 30% were induced solely by RTA expression, and another 37% can be upregulated by either viral protein This correlative analysis does not prove that these host genes are being upregulated by these viral proteins in vivo; this analysis is presented to outline the maximal potential contributions of each regulator to the observed patterns). Dissecting the relative contributions of each of these factors to the overall pattern of host mRNA accumulation will likely require genetic and functional genomic analyses of each coding region, carried out in the context of lytic KSHV replication
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
