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19 pages, 1977 KiB

Open AccessArticle

Synergistic Chromatin-Modifying Treatments Reactivate Latent HIV and Decrease Migration of Multiple Host-Cell Types

by Alexandra Blanco, Tarun Mahajan, Robert A. Coronado, Kelly Ma, Dominic R. Demma and Roy D. Dar

Viruses 2021, 13(6), 1097; https://0-doi-org.brum.beds.ac.uk/10.3390/v13061097 - 08 Jun 2021

Cited by 2 | Viewed by 3254

Abstract

Upon infection of its host cell, human immunodeficiency virus (HIV) establishes a quiescent and non-productive state capable of spontaneous reactivation. Diverse cell types harboring the provirus form a latent reservoir, constituting a major obstacle to curing HIV. Here, we investigate the effects of [...] Read more.

Upon infection of its host cell, human immunodeficiency virus (HIV) establishes a quiescent and non-productive state capable of spontaneous reactivation. Diverse cell types harboring the provirus form a latent reservoir, constituting a major obstacle to curing HIV. Here, we investigate the effects of latency reversal agents (LRAs) in an HIV-infected THP-1 monocyte cell line in vitro. We demonstrate that leading drug treatments synergize activation of the HIV long terminal repeat (LTR) promoter. We establish a latency model in THP-1 monocytes using a replication incompetent HIV reporter vector with functional Tat, and show that chromatin modifiers synergize with a potent transcriptional activator to enhance HIV reactivation, similar to T-cells. Furthermore, leading reactivation cocktails are shown to differentially affect latency reactivation and surface expression of chemokine receptor type 4 (CXCR4), leading to altered host cell migration. This study investigates the effect of chromatin-modifying LRA treatments on HIV latent reactivation and cell migration in monocytes. As previously reported in T-cells, epigenetic mechanisms in monocytes contribute to controlling the relationship between latent reactivation and cell migration. Ultimately, advanced “Shock and Kill” therapy needs to successfully target and account for all host cell types represented in a complex and composite latency milieu. Full article

(This article belongs to the Special Issue Epigenetics and Viral Infection)

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29 pages, 2536 KiB

Open AccessArticle

Mapping Influenza-Induced Posttranslational Modifications on Histones from CD8+ T Cells

by Svetlana Rezinciuc, Zhixin Tian, Si Wu, Shawna Hengel, Ljiljana Pasa-Tolic and Heather S. Smallwood

Viruses 2020, 12(12), 1409; https://0-doi-org.brum.beds.ac.uk/10.3390/v12121409 - 08 Dec 2020

Cited by 7 | Viewed by 2287

Abstract

T cell function is determined by transcriptional networks that are regulated by epigenetic programming via posttranslational modifications (PTMs) to histone proteins and DNA. Bottom-up mass spectrometry (MS) can identify histone PTMs, whereas intact protein analysis by MS can detect species missed by bottom-up [...] Read more.

T cell function is determined by transcriptional networks that are regulated by epigenetic programming via posttranslational modifications (PTMs) to histone proteins and DNA. Bottom-up mass spectrometry (MS) can identify histone PTMs, whereas intact protein analysis by MS can detect species missed by bottom-up approaches. We used a novel approach of online two-dimensional liquid chromatography-tandem MS with high-resolution reversed-phase liquid chromatography (RPLC), alternating electron transfer dissociation (ETD) and collision-induced dissociation (CID) on precursor ions to maximize fragmentation of uniquely modified species. The first online RPLC separation sorted histone families, then RPLC or weak cation exchange hydrophilic interaction liquid chromatography (WCX-HILIC) separated species heavily clad in PTMs. Tentative identifications were assigned by matching proteoform masses to predicted theoretical masses that were verified with tandem MS. We used this innovative approach for histone-intact protein PTM mapping (HiPTMap) to identify and quantify proteoforms purified from CD8 T cells after in vivo influenza infection. Activation significantly altered PTMs following influenza infection, histone maps changed as T cells migrated to the site of infection, and T cells responding to secondary infections had significantly more transcription enhancing modifications. Thus, HiPTMap identified and quantified proteoforms and determined changes in CD8 T cell histone PTMs over the course of infection. Full article

(This article belongs to the Special Issue Epigenetics and Viral Infection)

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21 pages, 13301 KiB

Open AccessArticle

Respiratory Syncytial Virus Infection Induces Chromatin Remodeling to Activate Growth Factor and Extracellular Matrix Secretion Pathways

by Xiaofang Xu, Dianhua Qiao, Morgan Mann, Roberto P. Garofalo and Allan R. Brasier

Viruses 2020, 12(8), 804; https://0-doi-org.brum.beds.ac.uk/10.3390/v12080804 - 26 Jul 2020

Cited by 19 | Viewed by 3774

Abstract

Lower respiratory tract infection (LRTI) with respiratory syncytial virus (RSV) is associated with reduced lung function through unclear mechanisms. In this study, we test the hypothesis that RSV infection induces genomic reprogramming of extracellular matrix remodeling pathways. For this purpose, we sought to [...] Read more.

Lower respiratory tract infection (LRTI) with respiratory syncytial virus (RSV) is associated with reduced lung function through unclear mechanisms. In this study, we test the hypothesis that RSV infection induces genomic reprogramming of extracellular matrix remodeling pathways. For this purpose, we sought to identify transcriptionally active open chromatin domains using assay for transposase-accessible-next generation sequencing (ATAC-Seq) in highly differentiated lower airway epithelial cells. High confidence nucleosome-free regions were those predicted independently using two peak-calling algorithms. In uninfected cells, ~12,650 high-confidence open chromatin regions were identified. These mapped to ~8700 gene bodies, whose genes functionally controlled organelle synthesis and Th2 pathways (IL6, TSLP). These latter cytokines are preferentially secreted by RSV-infected bronchiolar cells and linked to mucous production, obstruction, and atopy. By contrast, in RSV infection, we identify ~1700 high confidence open chromatin domains formed in 1120 genes, primarily in introns. These induced chromatin modifications are associated with complex gene expression profiles controlling tyrosine kinase growth factor signaling and extracellular matrix (ECM) secretory pathways. Of these, RSV induces formation of nucleosome-free regions on TGFB1/JUNB//FN1/MMP9 genes and the rate limiting enzyme in the hexosamine biosynthetic pathway (HBP), Glutamine-Fructose-6-Phosphate Transaminase 2 (GFPT2). RSV-induced open chromatin domains are highly enriched in AP1 binding motifs and overlap experimentally determined JUN peaks in GEO ChIP-Seq data sets. Our results provide a topographical map of chromatin accessibility and suggest a growth factor and AP1-dependent mechanism for upregulation of the HBP and ECM remodeling in lower epithelial cells that may be linked to long-term airway remodeling. Full article

(This article belongs to the Special Issue Epigenetics and Viral Infection)

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Review

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27 pages, 2559 KiB

Open AccessReview

De Novo Polycomb Recruitment: Lessons from Latent Herpesviruses

by Sara A. Dochnal, Alison K. Francois and Anna R. Cliffe

Viruses 2021, 13(8), 1470; https://0-doi-org.brum.beds.ac.uk/10.3390/v13081470 - 27 Jul 2021

Cited by 11 | Viewed by 2904

Abstract

The Human Herpesviruses persist in the form of a latent infection in specialized cell types. During latency, the herpesvirus genomes associate with cellular histone proteins and the viral lytic genes assemble into transcriptionally repressive heterochromatin. Although there is divergence in the nature of [...] Read more.

The Human Herpesviruses persist in the form of a latent infection in specialized cell types. During latency, the herpesvirus genomes associate with cellular histone proteins and the viral lytic genes assemble into transcriptionally repressive heterochromatin. Although there is divergence in the nature of heterochromatin on latent herpesvirus genomes, in general, the genomes assemble into forms of heterochromatin that can convert to euchromatin to permit gene expression and therefore reactivation. This reversible form of heterochromatin is known as facultative heterochromatin and is most commonly characterized by polycomb silencing. Polycomb silencing is prevalent on the cellular genome and plays a role in developmentally regulated and imprinted genes, as well as X chromosome inactivation. As herpesviruses initially enter the cell in an un-chromatinized state, they provide an optimal system to study how de novo facultative heterochromatin is targeted to regions of DNA and how it contributes to silencing. Here, we describe how polycomb-mediated silencing potentially assembles onto herpesvirus genomes, synergizing what is known about herpesvirus latency with facultative heterochromatin targeting to the cellular genome. A greater understanding of polycomb silencing of herpesviruses will inform on the mechanism of persistence and reactivation of these pathogenic human viruses and provide clues regarding how de novo facultative heterochromatin forms on the cellular genome. Full article

(This article belongs to the Special Issue Epigenetics and Viral Infection)

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19 pages, 2328 KiB

Open AccessReview

Are BET Inhibitors yet Promising Latency-Reversing Agents for HIV-1 Reactivation in AIDS Therapy?

by Thanarat Salahong, Christian Schwartz and Rungroch Sungthong

Viruses 2021, 13(6), 1026; https://0-doi-org.brum.beds.ac.uk/10.3390/v13061026 - 29 May 2021

Cited by 8 | Viewed by 4354

Abstract

AIDS first emerged decades ago; however, its cure, i.e., eliminating all virus sources, is still unachievable. A critical burden of AIDS therapy is the evasive nature of HIV-1 in face of host immune responses, the so-called “latency.” Recently, a promising approach, the “Shock [...] Read more.

AIDS first emerged decades ago; however, its cure, i.e., eliminating all virus sources, is still unachievable. A critical burden of AIDS therapy is the evasive nature of HIV-1 in face of host immune responses, the so-called “latency.” Recently, a promising approach, the “Shock and Kill” strategy, was proposed to eliminate latently HIV-1-infected cell reservoirs. The “Shock and Kill” concept involves two crucial steps: HIV-1 reactivation from its latency stage using a latency-reversing agent (LRA) followed by host immune responses to destroy HIV-1-infected cells in combination with reinforced antiretroviral therapy to kill the progeny virus. Hence, a key challenge is to search for optimal LRAs. Looking at epigenetics of HIV-1 infection, researchers proved that some bromodomains and extra-terminal motif protein inhibitors (BETis) are able to reactivate HIV-1 from latency. However, to date, only a few BETis have shown HIV-1-reactivating functions, and none of them have yet been approved for clinical trial. In this review, we aim to demonstrate the epigenetic roles of BETis in HIV-1 infection and HIV-1-related immune responses. Possible future applications of BETis and their HIV-1-reactivating properties are summarized and discussed. Full article

(This article belongs to the Special Issue Epigenetics and Viral Infection)

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17 pages, 977 KiB

Open AccessReview

Clinical Manifestations and Epigenetic Regulation of Oral Herpesvirus Infections

by Natalie Atyeo, Michelle D. Rodriguez, Bernadett Papp and Zsolt Toth

Viruses 2021, 13(4), 681; https://0-doi-org.brum.beds.ac.uk/10.3390/v13040681 - 15 Apr 2021

Cited by 12 | Viewed by 3965

Abstract

The oral cavity is often the first site where viruses interact with the human body. The oral epithelium is a major site of viral entry, replication and spread to other cell types, where chronic infection can be established. In addition, saliva has been [...] Read more.

The oral cavity is often the first site where viruses interact with the human body. The oral epithelium is a major site of viral entry, replication and spread to other cell types, where chronic infection can be established. In addition, saliva has been shown as a primary route of person-to-person transmission for many viruses. From a clinical perspective, viral infection can lead to several oral manifestations, ranging from common intraoral lesions to tumors. Despite the clinical and biological relevance of initial oral infection, little is known about the mechanism of regulation of the viral life cycle in the oral cavity. Several viruses utilize host epigenetic machinery to promote their own life cycle. Importantly, viral hijacking of host chromatin-modifying enzymes can also lead to the dysregulation of host factors and in the case of oncogenic viruses may ultimately play a role in promoting tumorigenesis. Given the known roles of epigenetic regulation of viral infection, epigenetic-targeted antiviral therapy has been recently explored as a therapeutic option for chronic viral infection. In this review, we highlight three herpesviruses with known roles in oral infection, including herpes simplex virus type 1, Epstein–Barr virus and Kaposi’s sarcoma-associated herpesvirus. We focus on the respective oral clinical manifestations of these viruses and their epigenetic regulation, with a specific emphasis on the viral life cycle in the oral epithelium. Full article

(This article belongs to the Special Issue Epigenetics and Viral Infection)

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14 pages, 972 KiB

Open AccessReview

The Crosstalk of Epigenetics and Metabolism in Herpesvirus Infection

by Yonggang Pei and Erle S. Robertson

Viruses 2020, 12(12), 1377; https://0-doi-org.brum.beds.ac.uk/10.3390/v12121377 - 01 Dec 2020

Cited by 12 | Viewed by 2770

Abstract

Epigenetics is a versatile player in manipulating viral infection and a potential therapeutic target for the treatment of viral-induced diseases. Both epigenetics and metabolism are crucial in establishing a highly specific transcriptional network, which may promote or suppress virus infection. Human herpesvirus infection [...] Read more.

Epigenetics is a versatile player in manipulating viral infection and a potential therapeutic target for the treatment of viral-induced diseases. Both epigenetics and metabolism are crucial in establishing a highly specific transcriptional network, which may promote or suppress virus infection. Human herpesvirus infection can induce a broad range of human malignancies and is largely dependent on the status of cellular epigenetics as well as its related metabolism. However, the crosstalk between epigenetics and metabolism during herpesvirus infection has not been fully explored. Here, we describe how epigenetic regulation of cellular metabolism affects herpesvirus infection and induces viral diseases. This further highlights the importance of epigenetics and metabolism during viral infection and provides novel insights into the development of targeted therapies. Full article

(This article belongs to the Special Issue Epigenetics and Viral Infection)

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16 pages, 1616 KiB

Open AccessReview

The Role of EBV-Induced Hypermethylation in Gastric Cancer Tumorigenesis

by Lyla J. Stanland and Micah A. Luftig

Viruses 2020, 12(11), 1222; https://0-doi-org.brum.beds.ac.uk/10.3390/v12111222 - 28 Oct 2020

Cited by 33 | Viewed by 4128

Abstract

Epstein–Barr-virus-associated Gastric Cancer (EBVaGC) comprises approximately 10% of global gastric cancers and is known to be the most hypermethylated of all tumor types. EBV infection has been shown to directly induce the hypermethylation of both the host and viral genome following initial infection [...] Read more.

Epstein–Barr-virus-associated Gastric Cancer (EBVaGC) comprises approximately 10% of global gastric cancers and is known to be the most hypermethylated of all tumor types. EBV infection has been shown to directly induce the hypermethylation of both the host and viral genome following initial infection of gastric epithelial cells. Many studies have been completed in an attempt to identify genes that frequently become hypermethylated and therefore significant pathways that become silenced to promote tumorigenesis. It is clear that EBV-induced hypermethylation silences key tumor suppressor genes, cell cycle genes and cellular differentiation factors to promote a highly proliferative and poorly differentiated cell population. EBV infection has been shown to induce methylation in additional malignancies including Nasopharyngeal Carcinoma and Burkitt’s Lymphoma though not to the same level as in EBVaGC. Lastly, some genes silenced in EBVaGC are common to other heavily methylated tumors such as colorectal and breast tumors; however, some genes are unique to EBVaGC and can provide insights into the major pathways involved in tumorigenesis. Full article

(This article belongs to the Special Issue Epigenetics and Viral Infection)

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15 pages, 1299 KiB

Open AccessReview

Regulation of the Human Papillomavirus Life Cycle by DNA Damage Repair Pathways and Epigenetic Factors

by Ekaterina Albert and Laimonis Laimins

Viruses 2020, 12(7), 744; https://0-doi-org.brum.beds.ac.uk/10.3390/v12070744 - 10 Jul 2020

Cited by 22 | Viewed by 4014

Abstract

Human papillomaviruses are the causative agents of cervical and other anogenital cancers along with approximately 60% of oropharyngeal cancers. These small double-stranded DNA viruses infect stratified epithelia and link their productive life cycles to differentiation. HPV proteins target cellular factors, such as those [...] Read more.

Human papillomaviruses are the causative agents of cervical and other anogenital cancers along with approximately 60% of oropharyngeal cancers. These small double-stranded DNA viruses infect stratified epithelia and link their productive life cycles to differentiation. HPV proteins target cellular factors, such as those involved in DNA damage repair, as well as epigenetic control of host and viral transcription to regulate the productive life cycle. HPVs constitutively activate the ATM and ATR DNA repair pathways and preferentially recruit these proteins to viral genomes to facilitate productive viral replication. In addition, the sirtuin deacetylases along with histone acetyltransferases, including Tip60, are targeted in HPV infections to regulate viral transcription and replication. These pathways provide potential targets for drug therapy to treat HPV-induced disease. Full article

(This article belongs to the Special Issue Epigenetics and Viral Infection)

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