Antagonistic determinants controlling replicative and latent states of human cytomegalovirus infection

Mahadevaiah Umashankar, Michael Rak, Farah Bughio, Patricia Zagallo, Katie Caviness, Felicia Goodrum

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

The mechanisms by which viruses persist and particularly those by which viruses actively contribute to their own latency have been elusive. Here we report the existence of opposing functions encoded by genes within a polycistronic locus of the human cytomegalovirus (HCMV) genome that regulate cell type-dependent viral fates: replication and latency. The locus, referred to as the UL133-UL138 (UL133/8) locus, encodes four proteins, pUL133, pUL135, pUL136, and pUL138. As part of the ULb' region of the genome, the UL133/8 locus is lost upon serial passage of clinical strains of HCMV in cultured fibroblasts and is therefore considered dispensable for replication in this context. Strikingly, we could not reconstitute infection in permissive fibroblasts from bacterial artificial chromosome clones of the HCMV genome where UL135 alone was disrupted. The loss of UL135 resulted in complex phenotypes and could ultimately be overcome by infection at high multiplicities. The requirement for UL135 but not the entire locus led us to hypothesize that another gene in this locus suppressed virus replication in the absence of UL135. The defect associated with the loss of UL135 was largely rescued by the additional disruption of the UL138 latency determinant, indicating a requirement for UL135 for virus replication when UL138 is expressed. In the CD34+ hematopoietic progenitor model of latency, viruses lacking only UL135 were defective for viral genome amplification and reactivation. Taken together, these data indicate that UL135 and UL138 comprise a molecular switch whereby UL135 is required to overcome UL138-mediated suppression of virus replication to balance states of latency and reactivation.

Original languageEnglish (US)
Pages (from-to)5987-6002
Number of pages16
JournalJournal of Virology
Volume88
Issue number11
DOIs
StatePublished - 2014

Fingerprint

Human herpesvirus 5
Cytomegalovirus Infections
Virus Replication
Cytomegalovirus
Human Genome
loci
virus replication
Fibroblasts
Virus Latency
Viruses
Serial Passage
Bacterial Artificial Chromosomes
genome
Viral Genome
Infection
viruses
Genes
fibroblasts
Clone Cells
Genome

ASJC Scopus subject areas

  • Immunology
  • Virology

Cite this

Antagonistic determinants controlling replicative and latent states of human cytomegalovirus infection. / Umashankar, Mahadevaiah; Rak, Michael; Bughio, Farah; Zagallo, Patricia; Caviness, Katie; Goodrum, Felicia.

In: Journal of Virology, Vol. 88, No. 11, 2014, p. 5987-6002.

Research output: Contribution to journalArticle

Umashankar, Mahadevaiah ; Rak, Michael ; Bughio, Farah ; Zagallo, Patricia ; Caviness, Katie ; Goodrum, Felicia. / Antagonistic determinants controlling replicative and latent states of human cytomegalovirus infection. In: Journal of Virology. 2014 ; Vol. 88, No. 11. pp. 5987-6002.
@article{e8e708f3c7a145c98a1dd8ad1cf205bc,
title = "Antagonistic determinants controlling replicative and latent states of human cytomegalovirus infection",
abstract = "The mechanisms by which viruses persist and particularly those by which viruses actively contribute to their own latency have been elusive. Here we report the existence of opposing functions encoded by genes within a polycistronic locus of the human cytomegalovirus (HCMV) genome that regulate cell type-dependent viral fates: replication and latency. The locus, referred to as the UL133-UL138 (UL133/8) locus, encodes four proteins, pUL133, pUL135, pUL136, and pUL138. As part of the ULb' region of the genome, the UL133/8 locus is lost upon serial passage of clinical strains of HCMV in cultured fibroblasts and is therefore considered dispensable for replication in this context. Strikingly, we could not reconstitute infection in permissive fibroblasts from bacterial artificial chromosome clones of the HCMV genome where UL135 alone was disrupted. The loss of UL135 resulted in complex phenotypes and could ultimately be overcome by infection at high multiplicities. The requirement for UL135 but not the entire locus led us to hypothesize that another gene in this locus suppressed virus replication in the absence of UL135. The defect associated with the loss of UL135 was largely rescued by the additional disruption of the UL138 latency determinant, indicating a requirement for UL135 for virus replication when UL138 is expressed. In the CD34+ hematopoietic progenitor model of latency, viruses lacking only UL135 were defective for viral genome amplification and reactivation. Taken together, these data indicate that UL135 and UL138 comprise a molecular switch whereby UL135 is required to overcome UL138-mediated suppression of virus replication to balance states of latency and reactivation.",
author = "Mahadevaiah Umashankar and Michael Rak and Farah Bughio and Patricia Zagallo and Katie Caviness and Felicia Goodrum",
year = "2014",
doi = "10.1128/JVI.03506-13",
language = "English (US)",
volume = "88",
pages = "5987--6002",
journal = "Journal of Virology",
issn = "0022-538X",
publisher = "American Society for Microbiology",
number = "11",

}

TY - JOUR

T1 - Antagonistic determinants controlling replicative and latent states of human cytomegalovirus infection

AU - Umashankar, Mahadevaiah

AU - Rak, Michael

AU - Bughio, Farah

AU - Zagallo, Patricia

AU - Caviness, Katie

AU - Goodrum, Felicia

PY - 2014

Y1 - 2014

N2 - The mechanisms by which viruses persist and particularly those by which viruses actively contribute to their own latency have been elusive. Here we report the existence of opposing functions encoded by genes within a polycistronic locus of the human cytomegalovirus (HCMV) genome that regulate cell type-dependent viral fates: replication and latency. The locus, referred to as the UL133-UL138 (UL133/8) locus, encodes four proteins, pUL133, pUL135, pUL136, and pUL138. As part of the ULb' region of the genome, the UL133/8 locus is lost upon serial passage of clinical strains of HCMV in cultured fibroblasts and is therefore considered dispensable for replication in this context. Strikingly, we could not reconstitute infection in permissive fibroblasts from bacterial artificial chromosome clones of the HCMV genome where UL135 alone was disrupted. The loss of UL135 resulted in complex phenotypes and could ultimately be overcome by infection at high multiplicities. The requirement for UL135 but not the entire locus led us to hypothesize that another gene in this locus suppressed virus replication in the absence of UL135. The defect associated with the loss of UL135 was largely rescued by the additional disruption of the UL138 latency determinant, indicating a requirement for UL135 for virus replication when UL138 is expressed. In the CD34+ hematopoietic progenitor model of latency, viruses lacking only UL135 were defective for viral genome amplification and reactivation. Taken together, these data indicate that UL135 and UL138 comprise a molecular switch whereby UL135 is required to overcome UL138-mediated suppression of virus replication to balance states of latency and reactivation.

AB - The mechanisms by which viruses persist and particularly those by which viruses actively contribute to their own latency have been elusive. Here we report the existence of opposing functions encoded by genes within a polycistronic locus of the human cytomegalovirus (HCMV) genome that regulate cell type-dependent viral fates: replication and latency. The locus, referred to as the UL133-UL138 (UL133/8) locus, encodes four proteins, pUL133, pUL135, pUL136, and pUL138. As part of the ULb' region of the genome, the UL133/8 locus is lost upon serial passage of clinical strains of HCMV in cultured fibroblasts and is therefore considered dispensable for replication in this context. Strikingly, we could not reconstitute infection in permissive fibroblasts from bacterial artificial chromosome clones of the HCMV genome where UL135 alone was disrupted. The loss of UL135 resulted in complex phenotypes and could ultimately be overcome by infection at high multiplicities. The requirement for UL135 but not the entire locus led us to hypothesize that another gene in this locus suppressed virus replication in the absence of UL135. The defect associated with the loss of UL135 was largely rescued by the additional disruption of the UL138 latency determinant, indicating a requirement for UL135 for virus replication when UL138 is expressed. In the CD34+ hematopoietic progenitor model of latency, viruses lacking only UL135 were defective for viral genome amplification and reactivation. Taken together, these data indicate that UL135 and UL138 comprise a molecular switch whereby UL135 is required to overcome UL138-mediated suppression of virus replication to balance states of latency and reactivation.

UR - http://www.scopus.com/inward/record.url?scp=84898836691&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84898836691&partnerID=8YFLogxK

U2 - 10.1128/JVI.03506-13

DO - 10.1128/JVI.03506-13

M3 - Article

C2 - 24623432

AN - SCOPUS:84898836691

VL - 88

SP - 5987

EP - 6002

JO - Journal of Virology

JF - Journal of Virology

SN - 0022-538X

IS - 11

ER -