Human Cytomegalovirus Decreases Major Histocompatibility Complex Class II by Regulating Class II Transactivator Transcript Levels in a Myeloid Cell Line

Sandhu, Praneet; Buchkovich, Nicholas J.

doi:10.1128/jvi.01901-19

Cited by 23 publications

(23 citation statements)

References 71 publications

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“…Thus, we hypothesized that treatment of infected cells with GW4869 would also affect the spread of HCMV. We tested the effect of GW4869 at a low MOI using a recombinant TB40/E strain that encodes green fluorescent protein (GFP) adjacent to the viral immediate early protein 2 separated by the T2A peptide (36). During infection with this virus, GFP-positive cells can be used to monitor virus spread through the monolayer after addition of the EV inhibitor GW4869 or dimethyl sulfoxide (DMSO) vehicle control.…”

Section: Resultsmentioning

confidence: 99%

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Human Cytomegalovirus Utilizes Extracellular Vesicles To Enhance Virus Spread

Streck

Zhao

Sundstrom

et al. 2020

J Virol

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Human cytomegalovirus (HCMV) manipulates cellular processes associated with secretory pathways within an infected cell to facilitate efficient viral replication. However, little is known about how HCMV infection alters the surrounding cellular environment to promote virus spread to uninfected cells. Extracellular vesicles (EVs) are key signaling molecules that are commonly altered in numerous disease states. Previous reports have shown that viruses commonly alter EVs, which can significantly impact infection. This study finds that HCMV modulates EV biogenesis machinery through upregulation of the endosomal sorting complex required for transport (ESCRT) proteins. This regulation appears to increase the activity of EV biogenesis, since HCMV-infected fibroblasts have increased vesicle release and altered vesicle size compared to EVs from uninfected cells. EVs generated through ESCRT-independent pathways are also beneficial to virus spread in fibroblasts, as treatment with the EV inhibitor GW4869 slowed the efficiency of HCMV spread. Importantly, the transfer of EVs purified from HCMV-infected cells enhanced virus spread. This suggests that HCMV modulates the EV pathway to transfer proviral signals to uninfected cells that prime the cellular environment for incoming infection and enhance the efficiency of virus spread. IMPORTANCE Human cytomegalovirus (HCMV) is a herpesvirus that leads to serious health consequences in neonatal or immunocompromised patients. Clinical management of infection in these at-risk groups remains a serious concern even with approved antiviral therapies available. It is necessary to increase our understanding of the cellular changes that occur during infection and their importance to virus spread. This may help to identify new targets during infection that will lead to the development of novel treatment strategies. Extracellular vesicles (EVs) represent an important method of intercellular communication in the human host. This study finds that HCMV manipulates this pathway to increase the efficiency of virus spread to uninfected cells. This finding defines a new layer of host manipulation induced by HCMV infection that leads to enhanced virus spread.

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Section: Resultsmentioning

confidence: 99%

“…Culture conditions were 37°C with 5% CO 2 . Wild-type TB40/E or the IE-2A-GFP derivative were used for all experiments (36). HCMV infections.…”

Section: Methodsmentioning

confidence: 99%

Human Cytomegalovirus Utilizes Extracellular Vesicles To Enhance Virus Spread

Streck

Zhao

Sundstrom

et al. 2020

J Virol

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“…Further evidence in a transfected cell line model system showed that CMV downregulates MHC class II expression on the cell surface via regulation of CIITA and independently of known CMV Class II modulators US2 and US3 (Cebulla et al, 2002). Recently, it has also been shown in kasumi-3 cells, a myeloid lineage tumor cell line, that reduction in endogenous expression of MHC class II is as a result of decreased CIITA transcription (Sandhu and Buchkovich, 2020). UL23 binds to the Stat effector molecule N-myc, preventing proper activation and translocation of the Stat1 homodimers required for IFN-γ signaling (Feng et al, 2018), while UL31 preferentially binds the cytosolic DNA sensor cGAS in a manner that results in inhibition of interferon-associated gene transcription (Huang et al, 2018).…”

Section: Evasion Via Downregulation Of Class II Transcriptional Activmentioning

confidence: 99%

The CD4+ T Cell Response to Human Cytomegalovirus in Healthy and Immunocompromised People

Lim

Jackson

Wills

2020

Front. Cell. Infect. Microbiol.

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While CD8+ T cells specific for human cytomegalovirus (HCMV) have been extensively studied in both healthy HCMV seropositive carriers and patients undergoing immunosuppression, studies on the CD4+ T cell response to HCMV had lagged behind. However, over the last few years there has been a significant advance in our understanding of the importance and contribution that CMV-specific CD4+ T cells make, not only to anti-viral immunity but also in the potential maintenance of latently infected cells. During primary infection with HCMV in adults, CD4+ T cells are important for the resolution of symptomatic disease, while persistent shedding of HCMV into urine and saliva is associated with a lack of HCMV specific CD4+ T cell response in young children. In immunosuppressed solid organ transplant recipients, a delayed appearance of HCMV-specific CD4+ T cells is associated with prolonged viremia and more severe clinical disease, while in haematopoietic stem cell transplant recipients, it has been suggested that HCMV-specific CD4+ T cells are required for HCMV-specific CD8+ T cells to exert their anti-viral effects. In addition, adoptive T-cell immunotherapy in transplant patients has shown that the presence of HCMV-specific CD4+ T cells is required for the maintenance of HCMV-specific CD8+ T cells. HCMV is a paradigm for immune evasion. The presence of viral genes that down-regulate MHC class II molecules and the expression of viral IL-10 both limit antigen presentation to CD4+ T cells, underlining the important role that this T cell subset has in antiviral immunity. This review will discuss the antigen specificity, effector function, phenotype and direct anti-viral properties of HCMV specific CD4+ T cells, as well as reviewing our understanding of the importance of this T cell subset in primary infection and long-term carriage in healthy individuals. In addition, their role and importance in congenital HCMV infection and during immunosuppression in both solid organ and haemopoietic stem cell transplantation is considered.

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“…Inhibition of MHC-II expression by varicella-zoster has also been observed [ 90 , 91 ]. Repression of CIITA by human cytomegalovirus (HCMV) and Epstein–Barr virus has also been shown [ 92 , 93 , 94 , 95 ]. Interference with the IFNγ pathway has been observed in infections with influenza viruses [ 96 , 97 ].…”

Section: Ciita In Diseasementioning

confidence: 99%

“…This inhibition was also independent of previously known viral MHC-II repressor proteins that intervene in the IFNγ-induced expression, such as the tegument protein pp65, the viral IL-10 homolog, and two proteins coded from unique short (US) regions, US2 and US3, failed to downregulate MHC-II expression. Single gene knock-out studies failed to find a responsible gene in the US region, thus suggesting that the cause may be a complex interaction of several proteins in this region or that the responsible factor is coded elsewhere [ 95 ].…”

Section: Ciita In Diseasementioning

confidence: 99%

The MHC Class II Transactivator CIITA: Not (Quite) the Odd-One-Out Anymore among NLR Proteins

Machado

Steimle

2021

IJMS

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In this review, we discuss the major histocompatibility complex (MHC) class II transactivator (CIITA), which is the master regulator of MHC class II gene expression. CIITA is the founding member of the mammalian nucleotide-binding and leucine-rich-repeat (NLR) protein family but stood apart for a long time as the only transcriptional regulator. More recently, it was found that its closest homolog, NLRC5 (NLR protein caspase activation and recruitment domain (CARD)-containing 5), is a regulator of MHC-I gene expression. Both act as non-DNA-binding activators through multiple protein–protein interactions with an MHC enhanceosome complex that binds cooperatively to a highly conserved combinatorial cis-acting module. Thus, the regulation of MHC-II expression is regulated largely through the differential expression of CIITA. In addition to the well-defined role of CIITA in MHC-II GENE regulation, we will discuss several other aspects of CIITA functions, such as its role in cancer, its role as a viral restriction element contributing to intrinsic immunity, and lastly, its very recently discovered role as an inhibitor of Ebola and SARS-Cov-2 virus replication. We will briefly touch upon the recently discovered role of NLRP3 as a transcriptional regulator, which suggests that transcriptional regulation is, after all, not such an unusual feature for NLR proteins.

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Human Cytomegalovirus Decreases Major Histocompatibility Complex Class II by Regulating Class II Transactivator Transcript Levels in a Myeloid Cell Line

Cited by 23 publications

References 71 publications

Human Cytomegalovirus Utilizes Extracellular Vesicles To Enhance Virus Spread

Human Cytomegalovirus Utilizes Extracellular Vesicles To Enhance Virus Spread

The CD4+ T Cell Response to Human Cytomegalovirus in Healthy and Immunocompromised People

The MHC Class II Transactivator CIITA: Not (Quite) the Odd-One-Out Anymore among NLR Proteins

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