The complex biology of human cytomegalovirus latency

Goodrum, Felicia

doi:10.1016/bs.aivir.2022.01.001

Cited by 20 publications

(20 citation statements)

References 250 publications

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“…Primary infection by HCMV occurs in fibroblast and epithelial cells of the skin or mucosa. Thereafter, the virus spreads and establishes life-long latent infection in myeloid lineage cells that is characterized by periodic reactivation events ( 15 ). HCMV is the leading cause of congenital birth defects and, in immunosuppressed adults, is linked to direct end-organ diseases and indirect posttransplantation effect ( 16 ).…”

Section: Introductionmentioning

confidence: 99%

Intercellular communication within the virus microenvironment affects the susceptibility of cells to secondary viral infections

et al. 2023

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Communication between infected cells and cells in the surrounding tissue is a determinant of viral spread. However, it remains unclear how cells in close or distant proximity to an infected cell respond to primary or secondary infections. We establish a cell-based system to characterize a virus microenvironment, distinguishing infected, neighboring, and distal cells. Cell sorting, microscopy, proteomics, and cell cycle assays allow resolving cellular features and functional consequences of proximity to infection. We show that human cytomegalovirus (HCMV) infection primes neighboring cells for both subsequent HCMV infections and secondary infections with herpes simplex virus 1 and influenza A. Neighboring cells exhibit mitotic arrest, dampened innate immunity, and altered extracellular matrix. Conversely, distal cells are poised to slow viral spread due to enhanced antiviral responses. These findings demonstrate how infection reshapes the microenvironment through intercellular signaling to facilitate spread and how spatial proximity to an infection guides cell fate.

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Section: Introductionmentioning

confidence: 99%

Intercellular communication within the virus microenvironment affects the susceptibility of cells to secondary viral infections

et al. 2023

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“…HCMV replicates productively in human primary fibroblasts, but also in epithelial and endothelial cells. HCMV latency has been best characterized in hematopoietic progenitor cells (CD34+ HPCs) and cells of the myeloid lineage (19). During latency, viral genomes are maintained, viral gene expression is restricted, and no new viral progeny are made.…”

Section: Introductionmentioning

confidence: 99%

“…HCMV reactivates in response to viral and host cues including cellular stress, inhibition of PI3K/Akt signaling, differentiation, or steroid treatment to re-initiate viral gene expression (4,(20)(21)(22)(23)(24)(25)(26). Viruses have evolved complex gene networks to sense and respond to multiple environmental stimuli that can feedback to impact viral gene expression (19,27,28).…”

Section: Introductionmentioning

confidence: 99%

“…While dispensable for replication in fibroblasts, these genes undoubtedly play important roles in other contexts of infection in the host (34)(35)(36)(37). We have characterized a 3.6-kb polycistronic gene locus within the ULb' region encoding four genes, UL133, UL135, UL136, and UL138, collectively referred to as the UL133-UL138 locus (19,38). On whole, the UL133-UL138 locus is suppressive to viral replication (34,35).…”

Section: Introductionmentioning

confidence: 99%

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UL135 and UL136 Epistasis Controls Reactivation of Human Cytomegalovirus

Moy

Collins-McMillen

Crawford

et al. 2023

Preprint

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Human cytomegalovirus (HCMV) is beta herpesvirus that persists indefinitely in the human host through a protracted, latent infection. The polycistronic UL133-UL138 gene locus of HCMV encodes genes regulating latency and reactivation. While UL138 is pro-latency, restricting virus replication in CD34+ hematopoietic progenitor cells (HPCs), UL135 overcomes this restriction for reactivation. By contrast, UL136 is expressed with later kinetics and encodes multiple protein isoforms with differential roles in latency and reactivation. Like UL135, the largest UL136 isoform, UL136p33, is required for reactivation from latency in hematopoietic cells. Furthermore, UL136p33 is unstable, and its instability is important for the establishment of latency and sufficient accumulation of UL136p33 is a checkpoint for reactivation. We hypothesized that stabilizing UL136p33 might overcome the requirement of UL135 for reactivation. To test this, we generated recombinant viruses lacking UL135 that expressed a stabilized variant of UL136p33. Stabilizing UL136p33 did not impact replication of the UL135-mutant virus in fibroblasts. However, in the context of infection in hematopoietic cells, stabilization of UL136p33 strikingly compensated for the loss of UL135, resulting in increased replication in CD34+ HPCs and in humanized NOD-scid IL2Rgammacnull (NSG) mice. This finding suggests that while UL135 is essential for reactivation, it functions at steps preceding the accumulation of UL136p33 and that stabilized expression of UL136p33 largely overcomes the requirement for UL135 in reactivation. Taken together, our genetic evidence indicates an epistatic relationship between UL136p33 and UL135 whereby UL135 may initiate events early in reactivation that will result in the accumulation of UL136p33 to a threshold required for productive reactivation.

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“…Esse fato era esperado em decorrência de que o plasma sanguíneo representa uma fração acelular do sangue (Goodrum, 2022). A identificação de HHV, por PCR, no plasma demonstraria a presença de virions, indicando a ocorrência de ciclo lítico (Johnson et al, 2000).…”

Section: Discussionunclassified

Avaliação de herpesvírus em sangue e saliva de pacientes cirróticos

Marinho¹

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The complex biology of human cytomegalovirus latency

Cited by 20 publications

References 250 publications

Intercellular communication within the virus microenvironment affects the susceptibility of cells to secondary viral infections

Intercellular communication within the virus microenvironment affects the susceptibility of cells to secondary viral infections

UL135 and UL136 Epistasis Controls Reactivation of Human Cytomegalovirus

Avaliação de herpesvírus em sangue e saliva de pacientes cirróticos

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