Human herpesvirus 8 (HHV-8) encodes non-structural proteins that regulate host cell antiviral mechanisms via multiple inhibitory interactions. We have found that viral interferon regulatory factor-1 (vIRF-1) inhibits the pro-apoptotic activity of BH3-only proteins (BOPs) including Bim and Bid by nuclear sequestration (Bim) or directly suppressing their induction of cytochrome c release from mitochondria. In addition, we have found that vIRF-1 can localize to mitochondria independently of its interaction with BOPs and specifically targets mitochondrial detergent-resistant membrane fractions (mitoDRMs), a type of lipid raft. MitoDRMs have been recently identified as a functionally important microdomain of mitochondria and emerged as an attractive target for the treatment of a variety of degenerative diseases and cancer. Despite the increasing significance of mitoDRMs, little is known about the role of mitoDRMs in virus infection. To our knowledge, vIRF-1 is the first viral protein known to target to mitoDRMs. Furthermore, our preliminary data have shown that the N-terminal proline-rich domain (PD, 1-75 residues) of vIRF-1 is essential for mitoDRM targeting and protects cells from mitochondrial damage. Also, vIRF-1 co-localizes with mitochondria in an aggregate resembling those occurring during mitophagy, indicating a possible role of vIRF-1 in mitochondria quality control and associated cell survival. To determine the contribution of vIRF-1 through mitoDRM targeting and cell protection to HHV-8 replication, this proposal focuses on examining: 1) the novel structural determinants of mitoDRM targeting by vIRF-1 PD;2) the molecular mechanisms of vIRF-1 mitoDRM anchoring and cell protection;3) the functional significance of mitoDRM-localized vIRF-1 in mitophagy and HHV-8 replication. This proposal will thus examine a novel paradigm of virus-host interaction, and potentially provide a basis for future development of novel antiviral agents based on the identified interactions and mechanisms.

Public Health Relevance

Human herpesvirus 8 (HHV-8) encoded interferon regulatory factor 1 (vIRF-1) protein is believed to play a defensive role against innate and acquired immune responses and antiviral apoptosis of host cells, thereby supporting productive viral infection and associated pathogenesis. We have shown that vIRF-1 confers resistance to cell death induced by pro-apoptotic proteins Bim and Bid by via direct binding and, importantly, localizes to functionally significant mitochondrial detergent resistant membranes (mitoDRMs), drug-targeting of which recently has been recognized as a potential strategy for the treatment of a variety of degenerative diseases and cancer. Our research will elucidate the molecular basis and functional consequences of mitoDRM targeting by HHV-8 vIRF-1, thereby providing fundamental new information about this novel type of virus-host interaction and revealing related molecular targets and strategies that could be used to attenuate productive virus infection and associated disease.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Exploratory/Developmental Grants (R21)
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Virology - A Study Section (VIRA)
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Beisel, Christopher E
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Johns Hopkins University
Internal Medicine/Medicine
Schools of Medicine
United States
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