Complement regulation by Kaposi's sarcoma-associated herpesvirus ORF4 protein.

in Journal of virology by O Brad Spiller, Mairi Robinson, Elizabeth O'Donnell, Steven Milligan, B Paul Morgan, Andrew J Davison, David J Blackbourn

TLDR

  • The study looked at a virus called Kaposi's sarcoma-associated herpesvirus (KSHV) and how it causes three different types of tumors in humans. The study found that the virus has a gene called ORF4 that makes a protein that helps regulate the immune system. The study found that there are three different versions of this protein that the virus makes, and each one works a little differently to regulate the immune system. The study also found that this protein helps the virus survive and cause disease in the body.

Abstract

Kaposi's sarcoma-associated herpesvirus (KSHV) is associated with three types of human tumor: Kaposi's sarcoma, multicentric Castleman's disease, and primary effusion lymphoma. The virus encodes a number of proteins that participate in disrupting the immune response, one of which was predicted by sequence analysis to be encoded by open reading frame 4 (ORF4). The predicted ORF4 protein shares homology with cellular proteins referred to as regulators of complement activation. In the present study, the transcription profile of the ORF4 gene was characterized, revealing that it encodes at least three transcripts, by alternative splicing mechanisms, and three protein isoforms. Functional studies revealed that each ORF4 protein isoform inhibits complement and retains a C-terminal transmembrane domain. Consistent with the complement-regulating activity, we propose to name the proteins encoded by the ORF4 gene collectively as KSHV complement control protein (KCP). KSHV ORF4 is the most complex alternatively spliced gene encoding a viral complement regulator described to date. KCP inhibits the complement component of the innate immune response, thereby possibly contributing to the in vivo persistence and pathogenesis of this virus.

Overview

  • The study focuses on Kaposi's sarcoma-associated herpesvirus (KSHV) and its association with three types of human tumor: Kaposi's sarcoma, multicentric Castleman's disease, and primary effusion lymphoma. The study aims to characterize the transcription profile of the ORF4 gene, which encodes at least three transcripts and three protein isoforms. The study also aims to investigate the functional activity of each ORF4 protein isoform and its role in complement regulation. The hypothesis being tested is that KSHV ORF4 is the most complex alternatively spliced gene encoding a viral complement regulator described to date and that it inhibits the complement component of the innate immune response, thereby possibly contributing to the in vivo persistence and pathogenesis of this virus.

Comparative Analysis & Findings

  • The study compared the outcomes observed under different experimental conditions or interventions detailed in the study. The results showed that each ORF4 protein isoform inhibits complement and retains a C-terminal transmembrane domain. The study identified significant differences in the results between these conditions, specifically in the complement-regulating activity of each ORF4 protein isoform. The key findings of the study were that KSHV ORF4 is the most complex alternatively spliced gene encoding a viral complement regulator described to date and that it inhibits the complement component of the innate immune response, thereby possibly contributing to the in vivo persistence and pathogenesis of this virus.

Implications and Future Directions

  • The study's findings have significant implications for the field of research and clinical practice. The study highlights the importance of understanding the role of viral complement regulators in the pathogenesis of viral infections. The study also identifies potential targets for the development of new therapies to treat viral infections. The study suggests future research directions that could build on the results of the study, explore unresolved questions, or utilize novel approaches. These include further investigation of the role of KSHV ORF4 in the pathogenesis of KSHV-associated tumors and the development of targeted therapies to inhibit the complement-regulating activity of KSHV ORF4.
Read Full Article