A novel human cytomegalovirus locus modulates cell type-specific outcomes of infection.

Clinical strains of HCMV encode 20 putative ORFs within a region of the genome termed ULb' that are postulated to encode functions related to persistence or immune evasion. We have previously identified ULb'-encoded pUL138 as necessary, but not sufficient, for HCMV latency in CD34+ hematop...

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Autores principales:	Mahadevaiah Umashankar, Alex Petrucelli, Louis Cicchini, Patrizia Caposio, Craig N Kreklywich, Michael Rak, Farah Bughio, Devorah C Goldman, Kimberly L Hamlin, Jay A Nelson, William H Fleming, Daniel N Streblow, Felicia Goodrum
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2011
Materias:	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/ad3d589c837c45a4a85163673d1fb1ed
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spelling	oai:doaj.org-article:ad3d589c837c45a4a85163673d1fb1ed2021-11-18T06:04:56ZA novel human cytomegalovirus locus modulates cell type-specific outcomes of infection.1553-73661553-737410.1371/journal.ppat.1002444https://doaj.org/article/ad3d589c837c45a4a85163673d1fb1ed2011-12-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22241980/?tool=EBIhttps://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374Clinical strains of HCMV encode 20 putative ORFs within a region of the genome termed ULb' that are postulated to encode functions related to persistence or immune evasion. We have previously identified ULb'-encoded pUL138 as necessary, but not sufficient, for HCMV latency in CD34+ hematopoietic progenitor cells (HPCs) infected in vitro. pUL138 is encoded on polycistronic transcripts that also encode 3 additional proteins, pUL133, pUL135, and pUL136, collectively comprising the UL133-UL138 locus. This work represents the first characterization of these proteins and identifies a role for this locus in infection. Similar to pUL138, pUL133, pUL135, and pUL136 are integral membrane proteins that partially co-localized with pUL138 in the Golgi during productive infection in fibroblasts. As expected of ULb' sequences, the UL133-UL138 locus was dispensable for replication in cultured fibroblasts. In CD34+ HPCs, this locus suppressed viral replication in HPCs, an activity attributable to both pUL133 and pUL138. Strikingly, the UL133-UL138 locus was required for efficient replication in endothelial cells. The association of this locus with three context-dependent phenotypes suggests an exciting role for the UL133-UL138 locus in modulating the outcome of viral infection in different contexts of infection. Differential profiles of protein expression from the UL133-UL138 locus correlated with the cell-type dependent phenotypes associated with this locus. We extended our in vitro findings to analyze viral replication and dissemination in a NOD-scid IL2Rγ(c) (null)-humanized mouse model. The UL133-UL138(NULL) virus exhibited an increased capacity for replication and/or dissemination following stem cell mobilization relative to the wild-type virus, suggesting an important role in viral persistence and spread in the host. As pUL133, pUL135, pUL136, and pUL138 are conserved in virus strains infecting higher order primates, but not lower order mammals, the functions encoded likely represent host-specific viral adaptations.Mahadevaiah UmashankarAlex PetrucelliLouis CicchiniPatrizia CaposioCraig N KreklywichMichael RakFarah BughioDevorah C GoldmanKimberly L HamlinJay A NelsonWilliam H FlemingDaniel N StreblowFelicia GoodrumPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 7, Iss 12, p e1002444 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
spellingShingle	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Mahadevaiah Umashankar Alex Petrucelli Louis Cicchini Patrizia Caposio Craig N Kreklywich Michael Rak Farah Bughio Devorah C Goldman Kimberly L Hamlin Jay A Nelson William H Fleming Daniel N Streblow Felicia Goodrum A novel human cytomegalovirus locus modulates cell type-specific outcomes of infection.
description	Clinical strains of HCMV encode 20 putative ORFs within a region of the genome termed ULb' that are postulated to encode functions related to persistence or immune evasion. We have previously identified ULb'-encoded pUL138 as necessary, but not sufficient, for HCMV latency in CD34+ hematopoietic progenitor cells (HPCs) infected in vitro. pUL138 is encoded on polycistronic transcripts that also encode 3 additional proteins, pUL133, pUL135, and pUL136, collectively comprising the UL133-UL138 locus. This work represents the first characterization of these proteins and identifies a role for this locus in infection. Similar to pUL138, pUL133, pUL135, and pUL136 are integral membrane proteins that partially co-localized with pUL138 in the Golgi during productive infection in fibroblasts. As expected of ULb' sequences, the UL133-UL138 locus was dispensable for replication in cultured fibroblasts. In CD34+ HPCs, this locus suppressed viral replication in HPCs, an activity attributable to both pUL133 and pUL138. Strikingly, the UL133-UL138 locus was required for efficient replication in endothelial cells. The association of this locus with three context-dependent phenotypes suggests an exciting role for the UL133-UL138 locus in modulating the outcome of viral infection in different contexts of infection. Differential profiles of protein expression from the UL133-UL138 locus correlated with the cell-type dependent phenotypes associated with this locus. We extended our in vitro findings to analyze viral replication and dissemination in a NOD-scid IL2Rγ(c) (null)-humanized mouse model. The UL133-UL138(NULL) virus exhibited an increased capacity for replication and/or dissemination following stem cell mobilization relative to the wild-type virus, suggesting an important role in viral persistence and spread in the host. As pUL133, pUL135, pUL136, and pUL138 are conserved in virus strains infecting higher order primates, but not lower order mammals, the functions encoded likely represent host-specific viral adaptations.
format	article
author	Mahadevaiah Umashankar Alex Petrucelli Louis Cicchini Patrizia Caposio Craig N Kreklywich Michael Rak Farah Bughio Devorah C Goldman Kimberly L Hamlin Jay A Nelson William H Fleming Daniel N Streblow Felicia Goodrum
author_facet	Mahadevaiah Umashankar Alex Petrucelli Louis Cicchini Patrizia Caposio Craig N Kreklywich Michael Rak Farah Bughio Devorah C Goldman Kimberly L Hamlin Jay A Nelson William H Fleming Daniel N Streblow Felicia Goodrum
author_sort	Mahadevaiah Umashankar
title	A novel human cytomegalovirus locus modulates cell type-specific outcomes of infection.
title_short	A novel human cytomegalovirus locus modulates cell type-specific outcomes of infection.
title_full	A novel human cytomegalovirus locus modulates cell type-specific outcomes of infection.
title_fullStr	A novel human cytomegalovirus locus modulates cell type-specific outcomes of infection.
title_full_unstemmed	A novel human cytomegalovirus locus modulates cell type-specific outcomes of infection.
title_sort	novel human cytomegalovirus locus modulates cell type-specific outcomes of infection.
publisher	Public Library of Science (PLoS)
publishDate	2011
url	https://doaj.org/article/ad3d589c837c45a4a85163673d1fb1ed
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A novel human cytomegalovirus locus modulates cell type-specific outcomes of infection.

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