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Article ; Online: A single polymorphic residue in humans underlies species-specific restriction of HSV-1 by the antiviral protein MxB.

Bayer, Avraham / Child, Stephanie J / Malik, Harmit S / Geballe, Adam P

2023 Volume 97, Issue 10, Page(s) e0083023

Abstract: Importance: Herpesviruses present a major global disease burden. Understanding the host cell mechanisms that block viral infections, as well as how viruses can evolve to counteract these host defenses, is critically important for understanding viral ... ...

Abstract	Importance: Herpesviruses present a major global disease burden. Understanding the host cell mechanisms that block viral infections, as well as how viruses can evolve to counteract these host defenses, is critically important for understanding viral disease pathogenesis. This study reveals that the major human variant of the antiviral protein myxovirus resistance protein B (MxB) inhibits the human pathogen herpes simplex virus (HSV-1), whereas a minor human variant and orthologous MxB genes from even closely related primates do not. Thus, in contrast to the many antagonistic virus-host interactions in which the virus is successful in thwarting the host's defense systems, here the human gene appears to be at least temporarily winning at this interface of the primate-herpesvirus evolutionary arms race. Our findings further show that a polymorphism at amino acid 83 in a small fraction of the human population is sufficient to abrogate MxB's ability to inhibit HSV-1, which could have important implications for human susceptibility to HSV-1 pathogenesis.
MeSH term(s)	Animals ; Humans ; Herpesvirus 1, Human/pathogenicity ; Herpesvirus 1, Human/physiology ; Host Microbial Interactions/genetics ; Myxovirus Resistance Proteins/genetics ; Myxovirus Resistance Proteins/metabolism ; Polymorphism, Genetic ; Primates/genetics ; Primates/virology ; Species Specificity
Chemical Substances	MX2 protein, human ; Myxovirus Resistance Proteins
Language	English
Publishing date	2023-10-05
Publishing country	United States
Document type	Comparative Study ; Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	80174-4
ISSN	1098-5514 ; 0022-538X
ISSN (online)	1098-5514
ISSN	0022-538X
DOI	10.1128/jvi.00830-23
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Article: A single polymorphic residue in humans underlies species-specific restriction of HSV-1 by the antiviral protein MxB.

Bayer, Avraham / Child, Stephanie J / Malik, Harmit S / Geballe, Adam P

bioRxiv : the preprint server for biology

2023

Abstract: Myxovirus resistance proteins (MxA and MxB) are interferon-induced proteins that exert antiviral activity against a diverse range of RNA and DNA viruses. In primates, MxA has been shown to inhibit myxoviruses, bunyaviruses, and hepatitis B virus, whereas ...

Abstract	Myxovirus resistance proteins (MxA and MxB) are interferon-induced proteins that exert antiviral activity against a diverse range of RNA and DNA viruses. In primates, MxA has been shown to inhibit myxoviruses, bunyaviruses, and hepatitis B virus, whereas MxB restricts retroviruses and herpesviruses. As a result of their conflicts with viruses, both genes have been undergoing diversifying selection during primate evolution. Here, we investigate how MxB evolution in primates has affected its restriction of herpesviruses. In contrast to human MxB, we find that most primate orthologs, including the closely related chimpanzee MxB, do not inhibit HSV-1 replication. However, all primate MxB orthologs tested restrict human cytomegalovirus. Through the generation of human and chimpanzee MxB chimeras we show that a single residue, M83, is the key determinant of restriction of HSV-1 replication. Humans are the only primate species known to encode a methionine at this position, whereas most other primate species encode a lysine. Residue 83 is also the most polymorphic residue in MxB in human populations, with M83 being the most common variant. However, ∼2.5% of human MxB alleles encode a threonine at this position, which does not restrict HSV-1. Thus, a single amino acid variant in MxB, which has recently risen to high frequency in humans, has endowed humans with HSV-1 antiviral activity. Importance: Herpesviruses present a major global disease burden. Understanding the host cell mechanisms that block viral infections as well as how viruses can evolve to counteract these host defenses is critically important for understanding viral disease pathogenesis, and for developing therapeutic tools aimed at treating or preventing viral infections. Additionally, understanding how these host and viral mechanisms adapt to counter one another can aid in identifying the risks of, and barriers to, cross-species transmission events. As highlighted by the recent SARS-CoV-2 pandemic, episodic transmission events can have severe consequences for human health. This study reveals that the major human variant of the antiviral protein MxB inhibits the human pathogen HSV-1, whereas human minor variants and orthologous MxB genes from even closely related primates do not. Thus, in contrast to the many antagonistic virus-host interactions in which the virus is successful in thwarting the defense systems of their native hosts, in this case the human gene appears to be at least temporarily winning at this interface of the primate-herpesviral evolutionary arms race. Our findings further show that a polymorphism at amino acid 83 in a small fraction of the human population is sufficient to abrogate MxB's ability to inhibit HSV-1, which could have important implications for human susceptibility to HSV-1 pathogenesis.
Language	English
Publishing date	2023-05-30
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.05.30.542951
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Article: Antagonism of Protein Kinase R by Large DNA Viruses.

Olson, Annabel T / Child, Stephanie J / Geballe, Adam P

Pathogens (Basel, Switzerland)

2022 Volume 11, Issue 7

Abstract: Decades of research on vaccinia virus (VACV) have provided a wealth of insights and tools that have proven to be invaluable in a broad range of studies of molecular virology and pathogenesis. Among the challenges that viruses face are intrinsic host ... ...

Abstract	Decades of research on vaccinia virus (VACV) have provided a wealth of insights and tools that have proven to be invaluable in a broad range of studies of molecular virology and pathogenesis. Among the challenges that viruses face are intrinsic host cellular defenses, such as the protein kinase R pathway, which shuts off protein synthesis in response to the dsRNA that accumulates during replication of many viruses. Activation of PKR results in phosphorylation of the α subunit of eukaryotic initiation factor 2 (eIF2α), inhibition of protein synthesis, and limited viral replication. VACV encodes two well-characterized antagonists, E3L and K3L, that can block the PKR pathway and thus enable the virus to replicate efficiently. The use of VACV with a deletion of the dominant factor, E3L, enabled the initial identification of PKR antagonists encoded by human cytomegalovirus (HCMV), a prevalent and medically important virus. Understanding the molecular mechanisms of E3L and K3L function facilitated the dissection of the domains, species-specificity, and evolutionary potential of PKR antagonists encoded by human and nonhuman CMVs. While remaining cognizant of the substantial differences in the molecular virology and replication strategies of VACV and CMVs, this review illustrates how VACV can provide a valuable guide for the study of other experimentally less tractable viruses.
Language	English
Publishing date	2022-07-12
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2695572-6
ISSN	2076-0817
ISSN	2076-0817
DOI	10.3390/pathogens11070790
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Article ; Online: Rapid adaptation to human protein kinase R by a unique genomic rearrangement in rhesus cytomegalovirus.

Child, Stephanie J / Greninger, Alexander L / Geballe, Adam P

PLoS pathogens

2021 Volume 17, Issue 1, Page(s) e1009088

Abstract: Cytomegaloviruses (CMVs) are generally unable to cross species barriers, in part because prolonged coevolution with one host species limits their ability to evade restriction factors in other species. However, the limitation in host range is incomplete. ... ...

Abstract	Cytomegaloviruses (CMVs) are generally unable to cross species barriers, in part because prolonged coevolution with one host species limits their ability to evade restriction factors in other species. However, the limitation in host range is incomplete. For example, rhesus CMV (RhCMV) can replicate in human cells, albeit much less efficiently than in rhesus cells. Previously we reported that the protein kinase R (PKR) antagonist encoded by RhCMV, rTRS1, has limited activity against human PKR but is nonetheless necessary and sufficient to enable RhCMV replication in human fibroblasts (HF). We now show that knockout of PKR in human cells or treatment with the eIF2B agonist ISRIB, which overcomes the translational inhibition resulting from PKR activation, augments RhCMV replication in HF, indicating that human PKR contributes to the inefficiency of RhCMV replication in HF. Serial passage of RhCMV in HF reproducibly selected for viruses with improved ability to replicate in human cells. The evolved viruses contain an inverted duplication of the terminal 6.8 kb of the genome, including rTRS1. The duplication replaces ~11.8 kb just downstream of an internal sequence element, pac1-like, which is very similar to the pac1 cleavage and packaging signal found near the terminus of the genome. Plaque-purified evolved viruses produced at least twice as much rTRS1 as the parental RhCMV and blocked the PKR pathway more effectively in HF. Southern blots revealed that unlike the parental RhCMV, viruses with the inverted duplication isomerize in a manner similar to HCMV and other herpesviruses that have internal repeat sequences. The apparent ease with which this duplication event occurs raises the possibility that the pac1-like site, which is conserved in Old World monkey CMV genomes, may serve a function in facilitating rapid adaptation to evolutionary obstacles.
MeSH term(s)	Animals ; Cytomegalovirus/genetics ; Cytomegalovirus/metabolism ; Cytomegalovirus/pathogenicity ; Cytomegalovirus Infections/genetics ; Cytomegalovirus Infections/metabolism ; Cytomegalovirus Infections/virology ; Fibroblasts/metabolism ; Fibroblasts/virology ; Gene Rearrangement ; Genome, Viral ; Host Specificity ; Humans ; Macaca mulatta ; Virus Replication ; eIF-2 Kinase/genetics ; eIF-2 Kinase/metabolism
Chemical Substances	EIF2AK2 protein, human (EC 2.7.11.1) ; eIF-2 Kinase (EC 2.7.11.1)
Language	English
Publishing date	2021-01-26
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2205412-1
ISSN	1553-7374 ; 1553-7374
ISSN (online)	1553-7374
ISSN	1553-7374
DOI	10.1371/journal.ppat.1009088
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Article ; Online: Translational buffering by ribosome stalling in upstream open reading frames.

Bottorff, Ty A / Park, Heungwon / Geballe, Adam P / Subramaniam, Arvind Rasi

PLoS genetics

2022 Volume 18, Issue 10, Page(s) e1010460

Abstract: Upstream open reading frames (uORFs) are present in over half of all human mRNAs. uORFs can potently regulate the translation of downstream open reading frames through several mechanisms: siphoning away scanning ribosomes, regulating re-initiation, and ... ...

Abstract	Upstream open reading frames (uORFs) are present in over half of all human mRNAs. uORFs can potently regulate the translation of downstream open reading frames through several mechanisms: siphoning away scanning ribosomes, regulating re-initiation, and allowing interactions between scanning and elongating ribosomes. However, the consequences of these different mechanisms for the regulation of protein expression remain incompletely understood. Here, we performed systematic measurements on the uORF-containing 5' UTR of the cytomegaloviral UL4 mRNA to test alternative models of uORF-mediated regulation in human cells. We find that a terminal diproline-dependent elongating ribosome stall in the UL4 uORF prevents decreases in main ORF protein expression when ribosome loading onto the mRNA is reduced. This uORF-mediated buffering is insensitive to the location of the ribosome stall along the uORF. Computational kinetic modeling based on our measurements suggests that scanning ribosomes dissociate rather than queue when they collide with stalled elongating ribosomes within the UL4 uORF. We identify several human uORFs that repress main ORF protein expression via a similar terminal diproline motif. We propose that ribosome stalls in uORFs provide a general mechanism for buffering against reductions in main ORF translation during stress and developmental transitions.
MeSH term(s)	Humans ; Open Reading Frames/genetics ; Ribosomes/genetics ; Ribosomes/metabolism ; 5' Untranslated Regions/genetics ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; Protein Processing, Post-Translational ; Protein Biosynthesis/genetics
Chemical Substances	5' Untranslated Regions ; RNA, Messenger
Language	English
Publishing date	2022-10-31
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, N.I.H., Extramural
ZDB-ID	2186725-2
ISSN	1553-7404 ; 1553-7390
ISSN (online)	1553-7404
ISSN	1553-7390
DOI	10.1371/journal.pgen.1010460
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Article: Antagonism of Protein Kinase R by Large DNA Viruses

Olson, Annabel T. / Child, Stephanie J. / Geballe, Adam P.

Pathogens. 2022 July 12, v. 11, no. 7

2022

Abstract	Decades of research on vaccinia virus (VACV) have provided a wealth of insights and tools that have proven to be invaluable in a broad range of studies of molecular virology and pathogenesis. Among the challenges that viruses face are intrinsic host cellular defenses, such as the protein kinase R pathway, which shuts off protein synthesis in response to the dsRNA that accumulates during replication of many viruses. Activation of PKR results in phosphorylation of the α subunit of eukaryotic initiation factor 2 (eIF2α), inhibition of protein synthesis, and limited viral replication. VACV encodes two well-characterized antagonists, E3L and K3L, that can block the PKR pathway and thus enable the virus to replicate efficiently. The use of VACV with a deletion of the dominant factor, E3L, enabled the initial identification of PKR antagonists encoded by human cytomegalovirus (HCMV), a prevalent and medically important virus. Understanding the molecular mechanisms of E3L and K3L function facilitated the dissection of the domains, species-specificity, and evolutionary potential of PKR antagonists encoded by human and nonhuman CMVs. While remaining cognizant of the substantial differences in the molecular virology and replication strategies of VACV and CMVs, this review illustrates how VACV can provide a valuable guide for the study of other experimentally less tractable viruses.
Keywords	DNA ; Human betaherpesvirus 5 ; Vaccinia virus ; antagonism ; dissection ; humans ; pathogenesis ; phosphorylation ; protein kinases ; protein synthesis ; virus replication ; viruses
Language	English
Dates of publication	2022-0712
Publishing place	Multidisciplinary Digital Publishing Institute
Document type	Article
ZDB-ID	2695572-6
ISSN	2076-0817
ISSN	2076-0817
DOI	10.3390/pathogens11070790
Database	NAL-Catalogue (AGRICOLA)

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Article: Gene amplification acts as a molecular foothold to facilitate cross-species adaptation and evasion of multiple antiviral pathways.

Banerjee, Shefali / Smith, Cathy / Geballe, Adam P / Rothenburg, Stefan / Kitzman, Jacob O / Brennan, Greg

Virus evolution

2022 Volume 8, Issue 2, Page(s) veac105

Abstract: Cross-species spillover events are responsible for many of the pandemics in human history including COVID-19; however, the evolutionary mechanisms that enable these events are poorly understood. We have previously modeled this process using a chimeric ... ...

Abstract	Cross-species spillover events are responsible for many of the pandemics in human history including COVID-19; however, the evolutionary mechanisms that enable these events are poorly understood. We have previously modeled this process using a chimeric vaccinia virus expressing the rhesus cytomegalovirus-derived protein kinase R (PKR) antagonist RhTRS1 in place of its native PKR antagonists: E3L and K3L (VACVΔEΔK + RhTRS1). Using this virus, we demonstrated that gene amplification of
Language	English
Publishing date	2022-11-14
Publishing country	England
Document type	Journal Article
ZDB-ID	2818949-8
ISSN	2057-1577
ISSN	2057-1577
DOI	10.1093/ve/veac105
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Article: Gene amplification acts as a molecular foothold to facilitate cross-species adaptation and evasion of multiple antiviral pathways.

Banerjee, Shefali / Smith, Cathy / Geballe, Adam / Rothenburg, Stefan / Kitzman, Jacob O / Brennan, Greg

bioRxiv : the preprint server for biology

2022

Abstract	Cross-species spillover events are responsible for many of the pandemics in human history including COVID-19; however, the evolutionary mechanisms that enable these events are poorly understood. We have previously modeled this process using a chimeric vaccinia virus expressing the rhesus cytomegalovirus-derived PKR antagonist RhTRS1 in place of its native PKR antagonists; E3L and K3L (VACVΔEΔK+RhTRS1). Using this virus, we demonstrated that gene amplification of
Language	English
Publishing date	2022-10-06
Publishing country	United States
Document type	Preprint
DOI	10.1101/2022.06.06.494757
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Article: Polypharmacology-based kinome screen identifies new regulators of KSHV reactivation.

Olson, Annabel T / Kang, Yuqi / Ladha, Anushka M / Lim, Chuan Bian / Lagunoff, Michael / Gujral, Taran S / Geballe, Adam P

bioRxiv : the preprint server for biology

2023

Abstract: Kaposi's sarcoma-associated herpesvirus (KSHV) causes several human diseases including Kaposi's sarcoma (KS), a leading cause of cancer in Africa and in patients with AIDS. KS tumor cells harbor KSHV predominantly in a latent form, while typically <5% ... ...

Abstract	Kaposi's sarcoma-associated herpesvirus (KSHV) causes several human diseases including Kaposi's sarcoma (KS), a leading cause of cancer in Africa and in patients with AIDS. KS tumor cells harbor KSHV predominantly in a latent form, while typically <5% contain lytic replicating virus. Because both latent and lytic stages likely contribute to cancer initiation and progression, continued dissection of host regulators of this biological switch will provide insights into fundamental pathways controlling the KSHV life cycle and related disease pathogenesis. Several cellular protein kinases have been reported to promote or restrict KSHV reactivation, but our knowledge of these signaling mediators and pathways is incomplete. We employed a polypharmacology-based kinome screen to identifiy specific kinases that regulate KSHV reactivation. Those identified by the screen and validated by knockdown experiments included several kinases that enhance lytic reactivation: ERBB2 (HER2 or Author summary: Kaposi's sarcoma-associated herpesvirus (KSHV) causes Kaposi's sarcoma, a cancer particularly prevalent in Africa. In cancer cells, the virus persists in a quiescent form called latency, in which only a few viral genes are made. Periodically, the virus switches into an active replicative cycle in which most of the viral genes are made and new virus is produced. What controls the switch from latency to active replication is not well understood, but cellular kinases, enzymes that control many cellular processes, have been implicated. Using a cell culture model of KSHV reactivation along with an innovative screening method that probes the effects of many cellular kinases simultaneously, we identified drugs that significantly limit KSHV reactivation, as well as specific kinases that either enhance or restrict KSHV replicative cycle. Among these were the ERBB kinases which are known to regulate growth of cancer cells. Understanding how these and other kinases contribute to the switch leading to production of more infectious virus helps us understand the mediators and mechanisms of KSHV diseases. Additionally, because kinase inhibitors are proving to be effective for treating other diseases including some cancers, identifying ones that restrict KSHV replicative cycle may lead to new approaches to treating KSHV-related diseases.
Language	English
Publishing date	2023-02-01
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.02.01.526589
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Article ; Online: An Evolutionary View of the Arms Race between Protein Kinase R and Large DNA Viruses.

Carpentier, Kathryn S / Geballe, Adam P

Journal of virology

2016 Volume 90, Issue 7, Page(s) 3280–3283

Abstract: To establish productive infections, viruses must counteract numerous cellular defenses that are poised to recognize viruses as nonself and to activate antiviral pathways. The opposing goals of host and viral factors lead to evolutionary arms races that ... ...

Abstract	To establish productive infections, viruses must counteract numerous cellular defenses that are poised to recognize viruses as nonself and to activate antiviral pathways. The opposing goals of host and viral factors lead to evolutionary arms races that can be illuminated by evolutionary and computational methods and tested in experimental models. Here we illustrate how this perspective has been contributing to our understanding of the interactions of the protein kinase R pathway with large DNA viruses.
MeSH term(s)	Animals ; DNA Virus Infections/enzymology ; DNA Virus Infections/immunology ; DNA Viruses/immunology ; Eukaryotic Initiation Factor-2/metabolism ; Evolution, Molecular ; Host-Pathogen Interactions/immunology ; Humans ; Interferons/immunology ; RNA, Double-Stranded/genetics ; RNA, Double-Stranded/metabolism ; eIF-2 Kinase/antagonists & inhibitors ; eIF-2 Kinase/genetics ; eIF-2 Kinase/metabolism
Chemical Substances	Eukaryotic Initiation Factor-2 ; RNA, Double-Stranded ; Interferons (9008-11-1) ; eIF-2 Kinase (EC 2.7.11.1)
Language	English
Publishing date	2016-01-20
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	80174-4
ISSN	1098-5514 ; 0022-538X
ISSN (online)	1098-5514
ISSN	0022-538X
DOI	10.1128/JVI.01996-15
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