Herpes simplex virus type 1 (HSV-1) R-loops are targets for APOBEC-mediated mutagenesis
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE312648 | GEO | 2026/03/09
REPOSITORIES: GEO
Similar Datasets
Project description:APOBEC cytidine deaminase enzymes play a crucial role in antiviral innate immunity as they introduce mutations in viral genomes, restrict viral replication, and promote host defense against infections. Special three-stranded nucleic acid structures, called R-loops, have been considered as efficient targets for APOBEC-mediated mutagenesis because they present an ideal substrate, a persistent single-stranded DNA, for the enzyme. However, the relationship between R-loops and APOBEC enzyme activity has not been verified and remains to be elucidated. Here, we reveal a mechanistic link between R-loop formation, APOBEC enzyme binding, and APOBEC mutagenesis at viral R-loop targets during virus infection. In a cellular model involving human T lymphoblastoid leukemia cells infected with Herpes simplex virus 1 (HSV-1), we show that APOBEC3A and APOBEC3G binding sites and mutagenesis signatures occur mainly in viral R-loop structures. C-to-T mutagenesis primarily targets R-loops, which are specifically concentrated in HSV-1 genes that are essential for virus assembly and function. Among these genes, we identified mutation hotspots resulting in amino acid changes, likely leading to inactivation of HSV-1 protein functions. Collectively, our findings show that viral R-loops serve as potent targets for APOBEC-induced mutagenesis, representing an effective strategy to inactivate essential viral proteins and compromise viral activity.
2026-03-11 | GSE284474 | GEO
Project description:APOBEC cytidine deaminase enzymes play a crucial role in antiviral innate immunity as they introduce mutations in viral genomes, restrict viral replication, and promote host defense against infections. Special three-stranded nucleic acid structures, called R-loops, have been considered as efficient targets for APOBEC-mediated mutagenesis because they present an ideal substrate, a persistent single-stranded DNA, for the enzyme. However, the relationship between R-loops and APOBEC enzyme activity has not been verified and remains to be elucidated. Here, we reveal a mechanistic link between R-loop formation, APOBEC enzyme binding, and APOBEC mutagenesis at viral R-loop targets during virus infection. In a cellular model involving human T lymphoblastoid leukemia cells infected with Herpes simplex virus 1 (HSV-1), we show that APOBEC3A and APOBEC3G binding sites and mutagenesis signatures occur mainly in viral R-loop structures. C-to-T mutagenesis primarily targets R-loops, which are specifically concentrated in HSV-1 genes that are essential for virus assembly and function. Among these genes, we identified mutation hotspots resulting in amino acid changes, likely leading to inactivation of HSV-1 protein functions. Collectively, our findings show that viral R-loops serve as potent targets for APOBEC-induced mutagenesis, representing an effective strategy to inactivate essential viral proteins and compromise viral activity.
2026-03-11 | GSE277996 | GEO
Project description:APOBEC cytidine deaminase enzymes play a crucial role in antiviral innate immunity as they introduce mutations in viral genomes, restrict viral replication, and promote host defense against infections. Special three-stranded nucleic acid structures, called R-loops, have been considered as efficient targets for APOBEC-mediated mutagenesis because they present an ideal substrate, a persistent single-stranded DNA, for the enzyme. However, the relationship between R-loops and APOBEC enzyme activity has not been verified and remains to be elucidated. Here, we reveal a mechanistic link between R-loop formation, APOBEC enzyme binding, and APOBEC mutagenesis at viral R-loop targets during virus infection. In a cellular model involving human T lymphoblastoid leukemia cells infected with Herpes simplex virus 1 (HSV-1), we show that APOBEC3A and APOBEC3G binding sites and mutagenesis signatures occur mainly in viral R-loop structures. C-to-T mutagenesis primarily targets R-loops, which are specifically concentrated in HSV-1 genes that are essential for virus assembly and function. Among these genes, we identified mutation hotspots resulting in amino acid changes, likely leading to inactivation of HSV-1 protein functions. Collectively, our findings show that viral R-loops serve as potent targets for APOBEC-induced mutagenesis, representing an effective strategy to inactivate essential viral proteins and compromise viral activity.
2026-03-11 | GSE277995 | GEO
Project description:The single-stranded DNA cytosine-to-uracil deaminase APOBEC3B is an antiviral protein implicated in cancer. However, its substrates in cells are not fully delineated. Here, APOBEC3B proteomics reveal interactions with a surprising number of R-loop factors. Biochemical experiments show APOBEC3B binding to R-loops in human cells and in vitro. Genetic experiments demonstrate R-loop increases in cells lacking APOBEC3B and decreases in cells overexpressing APOBEC3B. Genome-wide analyses show major changes in the overall landscape of physiological and stimulus-induced R-loops with thousands of differentially altered regions as well as binding of APOBEC3B to many of these sites. APOBEC3 mutagenesis impacts overexpressed genes and splice factor mutant tumors preferentially, and APOBEC3-attributed kataegis are enriched in RTCW consistent with APOBEC3B deamination. Taken together with the fact that APOBEC3B binds single-stranded DNA and RNA and preferentially deaminates DNA, these results support a mechanism in which APOBEC3B mediates R-loop homeostasis and contributes to R-loop mutagenesis in cancer.
2023-06-10 | GSE148581 | GEO
Project description:Herpes simplex virus 1 (HSV-1) is a widespread human pathogen that establishes lifelong infections, but understanding precise activity at each infection stage remains challenging. HSV-1 utilizes ubiquitination pathways to modulate cellular factors to facilitate its replication cycle, however, elucidating the cascades that follow host protein degradation and the subsequent impact on the host-virus equilibrium continues to be a complex endeavor. Here we reveal the multifaceted role of the DNA damage response protein RAP80 throughout HSV-1’s infection cycle. In early stages, RAP80 inhibits HSV-1 transcription by directly binding to the viral genome, blocking ICP4 (viral protein) binding to transcription factors. This interaction is regulated by phase separation via an intricate interplay between RAP80 and ICP0/ICP4. As infection progresses, the viral E3 ligase ICP0 degrades RAP80, dissolving phase separation, and allowing the formation of a mature viral replication compartment. In late infection stages, RAP80 is deubiquitinated by the viral deubiquitinase UL36USP, which restores cellular homeostasis and promotes HSV-1 survival. This process involves modulating the R-loop-cGAS-apoptosis pathway. These findings underscore the dynamic interplay between viral and host factors and the complex mechanisms used by HSV-1 to subvert host defenses, offering practical implications for the future development of antiviral strategies.
2024-11-13 | GSE281836 | GEO
Project description:After initial infection at mucosa, herpes simplex virus (HSV) establishes lifelong latency in neurons of the peripheral nervous system, which represents the source of recurrent disease. Current antiviral therapies reduce symptoms and viral shedding, but do not cure the infection. In contrast, gene editing offers the possibility to lethally mutate or even eliminate latent viral genomes. Delivery of gene editing enzymes by Adeno Associated Virus (AAV) vectors represents a promising approach to functionally curing HSV infection. In order to optimize in vivo gene therapy approaches it is necessary to understand which neuronal subtypes within peripheral ganglia are infected by HSV and which subtypes are efficiently targeted by various AAV serotypes. Here we use single cell RNA sequencing (scRNA-seq) to identify neurons expressing HSV genes as well as reporter genes for AAV1, AAV8, AAV-PhP.s, and AAV-Rh10 serotypes.
2020-06-05 | GSE151811 | GEO
Project description:The brain is highly sensitive to damage caused by infection and inflammation. Herpes simplex virus-1 (HSV-1) is a neurotropic virus and the cause of herpes simplex encephalitis. It is unknown whether neuron-specific antiviral factors control virus replication to prevent infection and excessive inflammatory responses, hence protecting the brain. Using genome-wide CRISPR screening for HSV-1 restriction factors, we identified TMEFF1, which is expressed specifically in CNS neurons and not regulated by type I interferon, as the best-known innate antiviral system controlling virus infections. Depletion of TMEFF1 in stem-cell-derived human neurons led to elevated viral replication and neuronal death upon HSV-1 infection. TMEFF1 blocked the HSV-1 replication cycle at the level of viral entry through interactions with Nectin-1 and non-muscle myosin heavy chain IIA/B, which are core proteins in virus-cell binding and virus-cell fusion, respectively. Importantly, Tmeff1-/- mice exhibited increased susceptibility to HSV-1 infection in the brain but not in the periphery. Within the brain, elevated viral load was observed specifically in neurons. Our study identifies TMEFF1 as a neuron-specific restriction factor essential for prevention of HSV-1 replication in the CNS.
2024-07-24 | GSE268182 | GEO
Project description:Herpes simplex virus type 1 (HSV-1) infects dendritic cells (DCs), professional antigen-presenting cells that initiate and regulate host antiviral responses. HSV-1 infects DCs limiting their maturation, migration to draining lymph nodes and T cell activation capacity, ultimately promotes their apoptosis. Here, we investigated the impact of HSV-1 infection over neutral lipid metabolism in DCs and their function. We found that HSV-1 significantly alters neutral lipid metabolism in infected DCs and promotes LD accumulation. Pharmacological inhibition of cholesterol ester synthesis, or fatty acid transporter proteins in infected DCs reduced LD accumulation and viral replication, enhanced DC viability and DC migration to draining lymph nodes and promoted DC priming of virus-specific CD8+ T cells. These findings highlight the role of neutral lipid metabolism in HSV-1-infected DCs and its impact over host immunity against this virus, underscoring lipid metabolism in DCs as a potential therapeutical target for triggering antiviral immunity against HSV-1.
2025-04-03 | MTBLS5163 | MetaboLights
Project description:Chronic viral infections are difficult to treat and new approaches, particularly those involving enhancing immune responses are needed. Herpes simplex virus (HSV) establishes latency, reactivates frequently, and breakthrough reactivation can occur despite suppressive antiviral therapy. Virus-specific T cells are important to control HSV, and activated T cells require increased metabolism of glutamine for their proliferation. We found that treatment of HSV-1 latently infected mice and HSV-2 infected guinea pigs with supplemental oral glutamine reduced virus reactivation. Transcriptome analysis of mice treated with glutamine showed that several interferon (IFN)-γ inducible genes were upregulated. Unlike wild-type mice, supplemental glutamine was ineffective in reducing the rate of HSV-1 reactivation in IFN-γ knock-out mice. Mice treated with glutamine had higher numbers of HSV-specific IFN-γ producing CD8 T cells in latently infected ganglia. Thus, glutamine may enhance the IFN-γ-associated immune response and reduce the rate of reactivation of latent virus infection.
2017-08-30 | GSE95715 | GEO
Project description:Chronic viral infections are difficult to treat and new approaches, particularly those involving enhancing immune responses are needed. Herpes simplex virus (HSV) establishes latency, reactivates frequently, and breakthrough reactivation can occur despite suppressive antiviral therapy. Virus-specific T cells are important to control HSV, and activated T cells require increased metabolism of glutamine for their proliferation. We found that treatment of HSV-1 latently infected mice and HSV-2 infected guinea pigs with supplemental oral glutamine reduced virus reactivation. Transcriptome analysis of mice treated with glutamine showed that several interferon (IFN)-γ inducible genes were upregulated. Unlike wild-type mice, supplemental glutamine was ineffective in reducing the rate of HSV-1 reactivation in IFN-γ knock-out mice. Mice treated with glutamine had higher numbers of HSV-specific IFN-γ producing CD8 T cells in latently infected ganglia. Thus, glutamine may enhance the IFN-γ-associated immune response and reduce the rate of reactivation of latent virus infection.
2017-08-30 | GSE95714 | GEO