Complex Interplay of the <italic toggle="yes">UL136</italic> Isoforms Balances Cytomegalovirus Replication and Latency

ABSTRACT Human cytomegalovirus (HCMV), a betaherpesvirus, persists indefinitely in the human host through poorly understood mechanisms. The UL136 gene is carried within a genetic locus important to HCMV latency termed the UL133/8 locus, which also carries UL133, UL135, and UL138. Previously, we demo...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Katie Caviness, Farah Bughio, Lindsey B. Crawford, Daniel N. Streblow, Jay A. Nelson, Patrizia Caposio, Felicia Goodrum
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2016
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/0d50ebf490fb45b2bca94d0540e3effb
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:0d50ebf490fb45b2bca94d0540e3effb
record_format	dspace
spelling	oai:doaj.org-article:0d50ebf490fb45b2bca94d0540e3effb2021-11-15T15:41:41ZComplex Interplay of the <italic toggle="yes">UL136</italic> Isoforms Balances Cytomegalovirus Replication and Latency10.1128/mBio.01986-152150-7511https://doaj.org/article/0d50ebf490fb45b2bca94d0540e3effb2016-05-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01986-15https://doaj.org/toc/2150-7511ABSTRACT Human cytomegalovirus (HCMV), a betaherpesvirus, persists indefinitely in the human host through poorly understood mechanisms. The UL136 gene is carried within a genetic locus important to HCMV latency termed the UL133/8 locus, which also carries UL133, UL135, and UL138. Previously, we demonstrated that UL136 is expressed as five protein isoforms ranging from 33-kDa to 19-kDa, arising from alternative transcription and, likely, translation initiation mechanisms. We previously showed that the UL136 isoforms are largely dispensable for virus infection in fibroblasts, a model for productive virus replication. In our current work, UL136 has emerged as a complex regulator of HCMV infection in multiple contexts of infection relevant to HCMV persistence: in an endothelial cell (EC) model of chronic infection, in a CD34+ hematopoietic progenitor cell (HPC) model of latency, and in an in vivo NOD-scid IL2Rγcnull humanized (huNSG) mouse model for latency. The 33- and 26-kDa isoforms promote replication, while the 23- and 19-kDa isoforms suppress replication in ECs, in CD34+ HPCs, and in huNSG mice. The role of the 25-kDa isoform is context dependent and influences the activity of the other isoforms. These isoforms localize throughout the secretory pathway, and loss of the 33- and 26-kDa UL136 isoforms results in virus maturation defects in ECs. This work reveals an intriguing functional interplay between protein isoforms that impacts virus replication, latency, and dissemination, contributing to the overall role of the UL133/8 locus in HCMV infection. IMPORTANCE The persistence of DNA viruses, and particularly of herpesviruses, remains an enigma because we have not completely defined the viral and host factors important to persistence. Human cytomegalovirus, a herpesvirus, persists in the absence of disease in immunocompetent individuals but poses a serious disease threat to transplant patients and the developing fetus. There is no vaccine, and current therapies do not target latent reservoirs. In an effort to define the viral factors important to persistence, we have studied viral genes with no known viral replication function in contexts important to HCMV persistence. Using models relevant to viral persistence, we demonstrate opposing roles of protein isoforms encoded by the UL136 gene in regulating latent and replicative states of infection. Our findings reveal an intriguing interplay between UL136 protein isoforms and define UL136 as an important regulator of HCMV persistence.Katie CavinessFarah BughioLindsey B. CrawfordDaniel N. StreblowJay A. NelsonPatrizia CaposioFelicia GoodrumAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 7, Iss 2 (2016)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Katie Caviness Farah Bughio Lindsey B. Crawford Daniel N. Streblow Jay A. Nelson Patrizia Caposio Felicia Goodrum Complex Interplay of the <italic toggle="yes">UL136</italic> Isoforms Balances Cytomegalovirus Replication and Latency
description	ABSTRACT Human cytomegalovirus (HCMV), a betaherpesvirus, persists indefinitely in the human host through poorly understood mechanisms. The UL136 gene is carried within a genetic locus important to HCMV latency termed the UL133/8 locus, which also carries UL133, UL135, and UL138. Previously, we demonstrated that UL136 is expressed as five protein isoforms ranging from 33-kDa to 19-kDa, arising from alternative transcription and, likely, translation initiation mechanisms. We previously showed that the UL136 isoforms are largely dispensable for virus infection in fibroblasts, a model for productive virus replication. In our current work, UL136 has emerged as a complex regulator of HCMV infection in multiple contexts of infection relevant to HCMV persistence: in an endothelial cell (EC) model of chronic infection, in a CD34+ hematopoietic progenitor cell (HPC) model of latency, and in an in vivo NOD-scid IL2Rγcnull humanized (huNSG) mouse model for latency. The 33- and 26-kDa isoforms promote replication, while the 23- and 19-kDa isoforms suppress replication in ECs, in CD34+ HPCs, and in huNSG mice. The role of the 25-kDa isoform is context dependent and influences the activity of the other isoforms. These isoforms localize throughout the secretory pathway, and loss of the 33- and 26-kDa UL136 isoforms results in virus maturation defects in ECs. This work reveals an intriguing functional interplay between protein isoforms that impacts virus replication, latency, and dissemination, contributing to the overall role of the UL133/8 locus in HCMV infection. IMPORTANCE The persistence of DNA viruses, and particularly of herpesviruses, remains an enigma because we have not completely defined the viral and host factors important to persistence. Human cytomegalovirus, a herpesvirus, persists in the absence of disease in immunocompetent individuals but poses a serious disease threat to transplant patients and the developing fetus. There is no vaccine, and current therapies do not target latent reservoirs. In an effort to define the viral factors important to persistence, we have studied viral genes with no known viral replication function in contexts important to HCMV persistence. Using models relevant to viral persistence, we demonstrate opposing roles of protein isoforms encoded by the UL136 gene in regulating latent and replicative states of infection. Our findings reveal an intriguing interplay between UL136 protein isoforms and define UL136 as an important regulator of HCMV persistence.
format	article
author	Katie Caviness Farah Bughio Lindsey B. Crawford Daniel N. Streblow Jay A. Nelson Patrizia Caposio Felicia Goodrum
author_facet	Katie Caviness Farah Bughio Lindsey B. Crawford Daniel N. Streblow Jay A. Nelson Patrizia Caposio Felicia Goodrum
author_sort	Katie Caviness
title	Complex Interplay of the <italic toggle="yes">UL136</italic> Isoforms Balances Cytomegalovirus Replication and Latency
title_short	Complex Interplay of the <italic toggle="yes">UL136</italic> Isoforms Balances Cytomegalovirus Replication and Latency
title_full	Complex Interplay of the <italic toggle="yes">UL136</italic> Isoforms Balances Cytomegalovirus Replication and Latency
title_fullStr	Complex Interplay of the <italic toggle="yes">UL136</italic> Isoforms Balances Cytomegalovirus Replication and Latency
title_full_unstemmed	Complex Interplay of the <italic toggle="yes">UL136</italic> Isoforms Balances Cytomegalovirus Replication and Latency
title_sort	complex interplay of the <italic toggle="yes">ul136</italic> isoforms balances cytomegalovirus replication and latency
publisher	American Society for Microbiology
publishDate	2016
url	https://doaj.org/article/0d50ebf490fb45b2bca94d0540e3effb
work_keys_str_mv	AT katiecaviness complexinterplayoftheitalictoggleyesul136italicisoformsbalancescytomegalovirusreplicationandlatency AT farahbughio complexinterplayoftheitalictoggleyesul136italicisoformsbalancescytomegalovirusreplicationandlatency AT lindseybcrawford complexinterplayoftheitalictoggleyesul136italicisoformsbalancescytomegalovirusreplicationandlatency AT danielnstreblow complexinterplayoftheitalictoggleyesul136italicisoformsbalancescytomegalovirusreplicationandlatency AT jayanelson complexinterplayoftheitalictoggleyesul136italicisoformsbalancescytomegalovirusreplicationandlatency AT patriziacaposio complexinterplayoftheitalictoggleyesul136italicisoformsbalancescytomegalovirusreplicationandlatency AT feliciagoodrum complexinterplayoftheitalictoggleyesul136italicisoformsbalancescytomegalovirusreplicationandlatency
_version_	1718427627146969088

Complex Interplay of the <italic toggle="yes">UL136</italic> Isoforms Balances Cytomegalovirus Replication and Latency

Ejemplares similares