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1.
J Pept Sci ; : e3596, 2024 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-38571326

RESUMO

The present review focuses on synthetic peptide-based vaccine strategies in the context of anticancer intervention, paying attention to critical aspects such as peptide epitope selection, adjuvant integration, and nuanced classification of synthetic peptide cancer vaccines. Within this discussion, we delve into the diverse array of synthetic peptide-based anticancer vaccines, each derived from tumor-associated antigens (TAAs), including melanoma antigen recognized by T cells 1 (Melan-A or MART-1), mucin 1 (MUC1), human epidermal growth factor receptor 2 (HER-2), tumor protein 53 (p53), human telomerase reverse transcriptase (hTERT), survivin, folate receptor (FR), cancer-testis antigen 1 (NY-ESO-1), and prostate-specific antigen (PSA). We also describe the synthetic peptide-based vaccines developed for cancers triggered by oncovirus, such as human papillomavirus (HPV), and hepatitis C virus (HCV). Additionally, the potential synergy of peptide-based vaccines with common therapeutics in cancer was considered. The last part of our discussion deals with the realm of the peptide-based vaccines delivery, highlighting its role in translating the most promising candidates into effective clinical strategies. Although this discussion does not cover all the ongoing peptide vaccine investigations, it aims at offering valuable insights into the chemical modifications and the structural complexities of anticancer peptide-based vaccines.

2.
Cells ; 13(6)2024 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-38534385

RESUMO

Approximately 15-20% of global cancer cases are attributed to virus infections. Oncoviruses employ various molecular strategies to enhance replication and persistence. Human cytomegalovirus (HCMV), acting as an initiator or promoter, enables immune evasion, supporting tumor growth. HCMV activates pro-oncogenic pathways within infected cells and direct cellular transformation. Thus, HCMV demonstrates characteristics reminiscent of oncoviruses. Cumulative evidence emphasizes the crucial roles of EZH2 and Myc in oncogenesis and stemness. EZH2 and Myc, pivotal regulators of cellular processes, gain significance in the context of oncoviruses and HCMV infections. This axis becomes a central focus for comprehending the mechanisms driving virus-induced oncogenesis. Elevated EZH2 expression is evident in various cancers, making it a prospective target for cancer therapy. On the other hand, Myc, deregulated in over 50% of human cancers, serves as a potent transcription factor governing cellular processes and contributing to tumorigenesis; Myc activates EZH2 expression and induces global gene expression. The Myc/EZH2 axis plays a critical role in promoting tumor growth in oncoviruses. Considering that HCMV has been shown to manipulate the Myc/EZH2 axis, there is emerging evidence suggesting that HCMV could be regarded as a potential oncovirus due to its ability to exploit this critical pathway implicated in tumorigenesis.


Assuntos
Infecções por Citomegalovirus , Neoplasias , Humanos , Citomegalovirus/genética , Regulação da Expressão Gênica , Carcinogênese , Transformação Celular Neoplásica , Proteína Potenciadora do Homólogo 2 de Zeste/genética
3.
Fish Shellfish Immunol ; 148: 109505, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38521144

RESUMO

The E11 cell line, derived from striped snakehead fish (Channa striata), possesses a distinctive feature: it is persistently infected with a C-type retrovirus. Notably, it exhibits high permissiveness to piscine nodavirus and the emerging tilapia lake virus (TiLV). Despite its popularity in TiLV research, the absence of genome assembly for the E11 cell line and Channa striata has constrained research on host-virus interactions. This study aimed to fill this gap by sequencing, assembling, and annotating the E11 cell line genome. Our efforts yielded a 600.5 Mb genome including 24 chromosomes with a BUSCO score of 98.8%. In addition, the complete proviral DNA sequence of snakehead retrovirus (SnRV) was identified in the E11 cell genome. Comparative genomic analysis between the E11 cell line and another snakehead species Channa argus revealed the loss of many immune-related gene families in the E11 cell genome, indicating a compromised immune response. We also conducted transcriptome analysis of mock- and TiLV-infected E11 cells, unveiling new perspectives on virus-virus and host-virus interactions. The TiLV infection suppressed the high expression of SnRV in E11 cells, and activated some other endogenous retroviruses. The protein-coding gene comparison revealed a pronounced up-regulation of genes involved in immune response, alongside a down-regulation of genes associated with specific metabolic processes. In summary, the genome assembly and annotation of the E11 cell line provide valuable resources to understand the SnRV and facilitate further studies on nodavirus and TiLV. The RNA-seq profiles shed light on the cellular mechanisms employed by fish cells in response to viral challenges, potentially guiding the development of therapeutic strategies against TiLV in aquaculture. This study also provides the first insights into the viral transcriptome profiles of endogenous SnRV and evading TiLV, enhancing our understanding of host-virus interactions in fish.


Assuntos
Doenças dos Peixes , Tilápia , Vírus , Animais , Retroviridae , Cromossomos , Perfilação da Expressão Gênica/veterinária
4.
Rev Med Virol ; 34(2): e2530, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38517354

RESUMO

A significant portion of human cancers are caused by oncoviruses (12%-25%). Oncoviruses employ various strategies to promote their replication and induce tumourigenesis in host cells, one of which involves modifying the gene expression patterns of the host cells, leading to the rewiring of genes and resulting in significant changes in cellular processes and signalling pathways. In recent studies, a specific mode of gene regulation known as circular RNA (circRNA)-mediated competing endogenous RNA (ceRNA) networks has emerged as a key player in this context. CircRNAs, a class of non-coding RNA molecules, can interact with other RNA molecules, such as mRNAs and microRNAs (miRNAs), through a process known as ceRNA crosstalk. This interaction occurs when circRNAs, acting as sponges, sequester miRNAs, thereby preventing them from binding to their target mRNAs and modulating their expression. By rewiring the host cell genome, oncoviruses have the ability to manipulate the expression and activity of circRNAs, thereby influencing the ceRNA networks that can profoundly impact cellular processes such as cell proliferation, differentiation, apoptosis, and immune responses. This review focuses on a comprehensive evaluation of the latest findings on the involvement of virus-induced reprogramming of host circRNA-mediated ceRNA networks in the development and pathophysiology of human viral cancers, including cervical cancer, gastric cancer, nasopharyngeal carcinoma, Kaposi's sarcoma, hepatocellular carcinoma, and diffuse large B cell lymphoma. Understanding these mechanisms can improve our knowledge of how oncoviruses contribute to human tumourigenesis and identify potential targets for developing optimised therapies and diagnostic tools for viral cancers.


Assuntos
Neoplasias Hepáticas , MicroRNAs , Humanos , MicroRNAs/genética , RNA Circular/genética , RNA Mensageiro/metabolismo , Retroviridae/genética , Retroviridae/metabolismo , Perfilação da Expressão Gênica/métodos , Carcinogênese/genética
5.
Arch Microbiol ; 206(3): 130, 2024 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-38416180

RESUMO

The human immunodeficiency virus (HIV) is a type of lentivirus that targets the human immune system and leads to acquired immunodeficiency syndrome (AIDS) at a later stage. Up to 2021, there are millions still living with HIV and many have lost their lives. To date, many anti-HIV compounds have been discovered in living organisms, especially plants and marine sponges. However, no treatment can offer a complete cure, but only suppressing it with a life-long medication, known as combined antiretroviral therapy (cART) or highly active antiretroviral therapy (HAART) which are often associated with various adverse effects. Also, it takes many years for a discovered compound to be approved for clinical use. Thus, by employing advanced technologies such as automation, conducting systematic screening and testing protocols may boost the discovery and development of potent and curative therapeutics for HIV infection/AIDS. In this review, we aim to summarize the antiretroviral therapies/compounds and their associated drawbacks since the discovery of azidothymidine. Additionally, we aim to provide an updated analysis of the most recent discoveries of promising antiretroviral candidates, along with an exploration of the current limitations within antiretroviral research. Finally, we intend to glean insightful perspectives and propose future research directions in this crucial area of study.


Assuntos
Infecções por HIV , Poríferos , Humanos , Animais , Retroviridae/genética , Infecções por HIV/tratamento farmacológico , Coleta de Dados , Antivirais/farmacologia , Antivirais/uso terapêutico
6.
Viruses ; 16(2)2024 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-38399943

RESUMO

Understanding the local epidemiology of feline leukaemia virus (FeLV) and feline immunodeficiency virus (FIV) in Hong Kong will inform retrovirus prevention strategies. Domestic cat hepadnavirus (DCH), a novel hepatitis-B-like virus, is commonly detected among client-owned cats in Hong Kong, but community cats have not been studied. The aims of this study were to investigate the frequency and potential risk factors for (i) FeLV and FIV among community and client-owned cats and (ii) perform molecular detection of DCH among community cats in Hong Kong. Blood samples from 713 cats were obtained from client-owned (n = 415, residual diagnostic) and community cats (n = 298, at trap-neuter-return). Point-of-care (POC) testing for FeLV antigen and feline immunodeficiency virus (FIV) anti-p15 and p24 antibodies was performed. FeLV-positive samples were progressed to p27 sandwich enzyme-linked immunosorbent assay. Whole blood DNA was tested with qPCRs for FeLV U3 and gag, and nested PCRs where additional information was required. DCH qPCR was performed on a subset of community cats (n = 193). A single, regressive, FeLV infection was detected in a client-owned cat (1/415 FeLV U3 qPCR positive, 0.2%, 95% CI 0.0-1.3%). Five/415 client-owned cats tested presumably false FeLV-antigen positive (qPCR negative). No markers of FeLV infection were detected in community cats (0/298; 0%). FIV seroprevalence was much higher in community cats (46/298, 15.4%) than in client-owned cats (13/415, 3.1%) (p < 0.001). Mixed breed was a risk factor for FIV infection in client-owned cats. Neither sex nor age were associated with FIV infection. DCH DNA was detected in 34/193 (17.6%) community cats (median viral load 6.32 × 103 copies/reaction). FeLV infection is rare in Hong Kong, negatively impacting the positive predictive value of diagnostic tests. FeLV-antigen testing remains the screening test of choice, but confirmation of a positive result using FeLV qPCR is essential. FIV infection is common in community cats and the absence of a sex predisposition, seen previously in cats managed similarly, raises questions about virus-transmission dynamics in these groups. DCH infection is very common in Hong Kong, both in client-owned and community cats, highlighting the importance of understanding the pathogenic potential of this virus for cats.


Assuntos
Doenças do Gato , Síndrome de Imunodeficiência Adquirida Felina , Hepadnaviridae , Vírus da Imunodeficiência Felina , Leucemia Felina , Humanos , Animais , Gatos , Retroviridae/genética , Hepadnaviridae/genética , Estudos Soroepidemiológicos , Hong Kong/epidemiologia , Vírus da Imunodeficiência Felina/genética , Vírus da Leucemia Felina/genética , Anticorpos Antivirais , DNA , Doenças do Gato/diagnóstico , Doenças do Gato/epidemiologia
7.
Cell Rep ; 43(3): 113775, 2024 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-38381606

RESUMO

In mammals, many retrotransposons are de-repressed during zygotic genome activation (ZGA). However, their functions in early development remain elusive largely due to the challenge to simultaneously manipulate thousands of retrotransposon insertions in embryos. Here, we applied CRISPR interference (CRISPRi) to perturb the long terminal repeat (LTR) MT2_Mm, a well-known ZGA and totipotency marker that exists in ∼2,667 insertions throughout the mouse genome. CRISPRi robustly perturbed 2,485 (∼93%) MT2_Mm insertions and 1,090 (∼55%) insertions of the closely related MT2C_Mm in 2-cell embryos. Remarkably, such perturbation caused downregulation of hundreds of ZGA genes and embryonic arrest mostly at the morula stage. Mechanistically, MT2 LTRs are globally enriched for open chromatin and H3K27ac and function as promoters/enhancers downstream of OBOX/DUX proteins. Thus, we not only provide direct evidence to support the functional importance of MT2 activation in development but also systematically define cis-regulatory function of MT2 in embryos by integrating functional perturbation and multi-omic analyses.


Assuntos
Sequências Reguladoras de Ácido Nucleico , Zigoto , Camundongos , Animais , Zigoto/metabolismo , Cromatina/metabolismo , Retroviridae , Retroelementos/genética , Sequências Repetidas Terminais/genética , Desenvolvimento Embrionário/genética , Regulação da Expressão Gênica no Desenvolvimento , Mamíferos/genética
8.
Retrovirology ; 21(1): 5, 2024 Feb 29.
Artigo em Inglês | MEDLINE | ID: mdl-38424561

RESUMO

Human immunodeficiency virus (HIV) and human T cell leukemia virus (HTLV) have replicative and latent stages of infection. The status of the viruses is dependent on the cells that harbour them and on different events that change the transcriptional and post-transcriptional events. Non-coding (nc)RNAs are key factors in the regulation of retrovirus replication cycles. Notably, micro (mi)RNAs and long non-coding (lnc)RNAs are important regulators that can induce switches between active transcription-replication and latency of retroviruses and have important impacts on their pathogenesis. Here, we review the functions of miRNAs and lncRNAs in the context of HIV and HTLV. We describe how specific miRNAs and lncRNAs are involved in the regulation of the viruses' transcription, post-transcriptional regulation and latency. We further discuss treatment strategies using ncRNAs for HIV and HTLV long remission, reactivation or possible cure.


Assuntos
Infecções por HIV , MicroRNAs , RNA Longo não Codificante , Humanos , MicroRNAs/genética , RNA Longo não Codificante/genética , HIV , Regulação da Expressão Gênica , RNA não Traduzido/genética , Deltaretrovirus , Retroviridae/genética
9.
Nat Med ; 30(2): 488-497, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38355973

RESUMO

Adenosine deaminase (ADA) deficiency leads to severe combined immunodeficiency (SCID). Previous clinical trials showed that autologous CD34+ cell gene therapy (GT) following busulfan reduced-intensity conditioning is a promising therapeutic approach for ADA-SCID, but long-term data are warranted. Here we report an analysis on long-term safety and efficacy data of 43 patients with ADA-SCID who received retroviral ex vivo bone marrow-derived hematopoietic stem cell GT. Twenty-two individuals (median follow-up 15.4 years) were treated in the context of clinical development or named patient program. Nineteen patients were treated post-marketing authorization (median follow-up 3.2 years), and two additional patients received mobilized peripheral blood CD34+ cell GT. At data cutoff, all 43 patients were alive, with a median follow-up of 5.0 years (interquartile range 2.4-15.4) and 2 years intervention-free survival (no need for long-term enzyme replacement therapy or allogeneic hematopoietic stem cell transplantation) of 88% (95% confidence interval 78.7-98.4%). Most adverse events/reactions were related to disease background, busulfan conditioning or immune reconstitution; the safety profile of the real world experience was in line with premarketing cohort. One patient from the named patient program developed a T cell leukemia related to treatment 4.7 years after GT and is currently in remission. Long-term persistence of multilineage gene-corrected cells, metabolic detoxification, immune reconstitution and decreased infection rates were observed. Estimated mixed-effects models showed that higher dose of CD34+ cells infused and younger age at GT affected positively the plateau of CD3+ transduced cells, lymphocytes and CD4+ CD45RA+ naive T cells, whereas the cell dose positively influenced the final plateau of CD15+ transduced cells. These long-term data suggest that the risk-benefit of GT in ADA remains favorable and warrant for continuing long-term safety monitoring. Clinical trial registration: NCT00598481 , NCT03478670 .


Assuntos
Agamaglobulinemia , Transplante de Células-Tronco Hematopoéticas , Imunodeficiência Combinada Severa , Humanos , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/terapia , Adenosina Desaminase/genética , Adenosina Desaminase/uso terapêutico , Bussulfano/efeitos adversos , Terapia Genética , Retroviridae/genética
10.
Nucleic Acids Res ; 52(5): 2625-2647, 2024 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-38165048

RESUMO

Translation initiation of the human immunodeficiency virus-type 1 (HIV-1) genomic mRNA (vRNA) is cap-dependent or mediated by an internal ribosome entry site (IRES). The HIV-1 IRES requires IRES-transacting factors (ITAFs) for function. In this study, we evaluated the role of the heterogeneous nuclear ribonucleoprotein K (hnRNPK) as a potential ITAF for the HIV-1 IRES. In HIV-1-expressing cells, the depletion of hnRNPK reduced HIV-1 vRNA translation. Furthermore, both the depletion and overexpression of hnRNPK modulated HIV-1 IRES activity. Phosphorylations and protein arginine methyltransferase 1 (PRMT1)-induced asymmetrical dimethylation (aDMA) of hnRNPK strongly impacted the protein's ability to promote the activity of the HIV-1 IRES. We also show that hnRNPK acts as an ITAF for the human T cell lymphotropic virus-type 1 (HTLV-1) IRES, present in the 5'UTR of the viral sense mRNA, but not for the IRES present in the antisense spliced transcript encoding the HTLV-1 basic leucine zipper protein (sHBZ). This study provides evidence for a novel role of the host hnRNPK as an ITAF that stimulates IRES-mediated translation initiation for the retroviruses HIV-1 and HTLV-1.


Assuntos
Ribonucleoproteínas Nucleares Heterogêneas Grupo K , Retroviridae , Humanos , Regiões 5' não Traduzidas , Ribonucleoproteínas Nucleares Heterogêneas Grupo K/genética , Ribonucleoproteínas Nucleares Heterogêneas Grupo K/metabolismo , Sítios Internos de Entrada Ribossomal/genética , Fosforilação , Biossíntese de Proteínas , Processamento de Proteína Pós-Traducional , Proteína-Arginina N-Metiltransferases/metabolismo , Proteínas Repressoras/metabolismo , Retroviridae/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
11.
Clin Epigenetics ; 16(1): 11, 2024 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-38212818

RESUMO

BACKGROUND: As an oncovirus, EBV is associated with multiple cancers, including solid tumors and hematological malignancies. EBV methylation plays an important role in regulating tumor occurrence. However, the EBV methylation profiles in EBV-associated tumor tissues are poorly understood. RESULTS: In this study, EBV methylation capture sequencing was conducted in several different tumor tissue samples, including NPC, EBVaGC, lung LELC and parotid LELC. Besides, EBV capture sequencing and following qMSP were performed on nasopharyngeal brushing samples from NPC and nasal NKTCL patients. Our results showed that the EBV genome among different types of tumors displayed specific methylation patterns. Among the four types of tumors from epithelial origin (NPC, EBVaGC, lung LELC and parotid LELC), the most significant differences were found between EBVaGC and the others. For example, in EBVaGC, all CpG sites within 1,44,189-1,45,136 bp of the EBV genome sequence on gene RPMS1 were hyper-methylated compared to the others. Differently, significant differences of EBV CpG sites, particularly those located on gene BILF2, were observed between NPC and nasal NKTCL patients in nasopharyngeal brushing samples. Further, the methylated level of BILF2 was further detected using qMSP, and a diagnostic model distinguishing NPC and nasal NKTCL was established. The AUC of the model was 0.9801 (95% CI 0.9524-1.0000), with the sensitivity and specificity of 98.81% (95% CI 93.63-99.94%) and 76.92% (95% CI 49.74-91.82%), respectively. CONCLUSIONS: Our study reveals more clues for further understanding the pathogenesis of EBV, and provides a possibility for distinguishing EBV-related tumor by detecting specific EBV CpG sites.


Assuntos
Carcinoma , Linfoma de Células T , Neoplasias Nasofaríngeas , Humanos , Carcinoma Nasofaríngeo/genética , Herpesvirus Humano 4/genética , Metilação de DNA , Carcinoma/genética , Neoplasias Nasofaríngeas/diagnóstico , Neoplasias Nasofaríngeas/genética , Linfoma de Células T/genética
12.
Dev Biol ; 508: 1-7, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38218394

RESUMO

Retroviral-mediated misexpression in chicken embryos has been a powerful research tool for developmental biologists in the last two decades. In the RCASBP retroviral vectors that are widely used for in vivo somatic transgenesis, a coding sequence of interest is under the transcriptional control of a strong viral promoter in the long terminal repeat. While this has proven to be effective for studying secreted signalling proteins, interpretation of the mechanisms of action of nuclear factors is more difficult using this system since it is not clear whether phenotypic effects are cell-autonomous or not, and therefore whether they represent a function of the endogenous protein. Here, we report the consequences of retroviral expression using the RCANBP backbone, in which the transcription factor Dlx5 is expressed under the control of chondrocyte-specific regulatory sequences from the Col2a1 gene. To our knowledge, this is the first demonstration of a tissue-specific phenotype in the chicken embryo.


Assuntos
Galinhas , Fatores de Transcrição , Animais , Embrião de Galinha , Galinhas/genética , Fatores de Transcrição/genética , Técnicas de Transferência de Genes , Retroviridae/genética , Regulação da Expressão Gênica , Vetores Genéticos
13.
Methods Mol Biol ; 2773: 9-24, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38236532

RESUMO

T-cell acute lymphoblastic leukemia (T-ALL) is primarily a NOTCH1-driven disease, which represents approximately 15% of pediatric and 25% of adult newly diagnosed ALL cases. Gain-of-function NOTCH1 mutations are highly prevalent in T-ALL contributing to almost 60% of the cases. The protocol presented here describes a method for in vivo T-ALL transformation driven by the retroviral transduction of hematopoietic progenitors with oncogenic mutant forms NOTCH1 and subsequent transplant into recipient mice. This T-ALL transformation model allows the interaction between the leukemia cells and the bone marrow microenvironment, better recapitulating the physiological conditions that promote the development of the human disease, providing a versatile tool for both experimental therapeutics and functional genetics studies on T-ALL.


Assuntos
Leucemia-Linfoma Linfoblástico de Células T Precursoras , Transplantes , Adulto , Humanos , Animais , Criança , Camundongos , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Mutação , Retroviridae , Linfócitos T , Microambiente Tumoral , Receptor Notch1/genética
14.
J Med Virol ; 96(1): e29363, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38178584

RESUMO

Oncovirus infections account for an estimated 12%-20% of human cancers worldwide. High-risk human papillomavirus (HPV) infection is the etiological agent of some malignancies such as cervical, oropharyngeal, anal, penile, vaginal, and vulvar cancers. However, HPV infection is not the only cause of these cancers or may not be sufficient to initiate cancer development. Actually, certain other risk factors including additional oncoviruses coinfections have been reported to increase the risk of patients exposed to HPV for developing different HPV-related cancers. In the current review, we summarize recent findings about coinfections with different oncoviruses in HPV+ patients from both clinical and mechanistic studies. We believe such efforts may lead to an interesting direction for improving our understanding and developing new treatments for virus-induced cancers.


Assuntos
Neoplasias do Ânus , Coinfecção , Neoplasias Orofaríngeas , Infecções por Papillomavirus , Neoplasias Penianas , Neoplasias do Colo do Útero , Masculino , Feminino , Humanos , Infecções por Papillomavirus/complicações , Coinfecção/complicações , Neoplasias Orofaríngeas/complicações , Neoplasias do Ânus/etiologia
15.
PLoS Pathog ; 20(1): e1011640, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38215165

RESUMO

Retroviral reverse transcription starts within the capsid and uncoating and reverse transcription are mutually dependent. There is still debate regarding the timing and cellular location of HIV's uncoating and reverse transcription and whether it occurs solely in the cytoplasm, nucleus or both. HIV can infect non-dividing cells because there is active transport of the preintegration complex (PIC) across the nuclear membrane, but Murine Leukemia Virus (MLV) is thought to depend on cell division for replication and whether MLV uncoating and reverse transcription is solely cytoplasmic has not been studied. Here, we used NIH3T3 and primary mouse dendritic cells to determine where the different stages of reverse transcription occur and whether cell division is needed for nuclear entry. Our data strongly suggest that in both NIH3T3 cells and dendritic cells (DCs), the initial step of reverse transcription occurs in the cytoplasm. However, we detected MLV RNA/DNA hybrid intermediates in the nucleus of dividing NIH3T3 cells and non-dividing DCs, suggesting that reverse transcription can continue after nuclear entry. We also confirmed that the MLV PIC requires cell division to enter the nucleus of NIH3T3 cells. In contrast, we show that MLV can infect non-dividing primary DCs, although integration of MLV DNA in DCs still required the viral p12 protein. Knockdown of several nuclear pore proteins dramatically reduced the appearance of integrated MLV DNA in DCs but not NIH3T3 cells. Additionally, MLV capsid associated with the nuclear pore proteins NUP358 and NUP62 during infection. These findings suggest that simple retroviruses, like the complex retrovirus HIV, gain nuclear entry by traversing the nuclear pore complex in non-mitotic cells.


Assuntos
Infecções por HIV , Complexo de Proteínas Formadoras de Poros Nucleares , Animais , Camundongos , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Células NIH 3T3 , Vírus da Leucemia Murina/genética , Proteínas Virais , Proteínas do Capsídeo , Retroviridae , DNA , Células Dendríticas
16.
Genes Genet Syst ; 98(6): 321-336, 2024 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-38220159

RESUMO

In the course of evolution, the most highly developed organ is likely the brain, which has become more complex over time and acquired diverse forms and functions in different species. In particular, mammals have developed complex and high-functioning brains, and it has been reported that several genes derived from retroviruses were involved in mammalian brain evolution, that is, generating the complexity of the nervous system. Especially, the sushi-ichi-related retrotransposon homolog (SIRH)/retrotransposon gag-like (RTL) genes have been suggested to play a role in the evolutionary processes shaping brain morphology and function in mammals. Genetic mutation and altered expression of genes are linked to neurological disorders, highlighting how the acquisition of virus-derived genes in mammals has both driven brain evolution and imposed a susceptibility to diseases. This review provides an overview of the functions, diversity, evolution and diseases associated with SIRH/RTL genes in the nervous system. The contribution of retroviruses to brain evolution is an important research topic in evolutionary biology and neuroscience, and further insights are expected to be gained through future studies.


Assuntos
Retroelementos , Retroviridae , Animais , Retroviridae/genética , Retroelementos/genética , Mamíferos/genética , Sistema Nervoso , Evolução Molecular
17.
Nat Commun ; 15(1): 299, 2024 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-38182622

RESUMO

Viruses that carry a positive-sense, single-stranded (+ssRNA) RNA translate their genomes soon after entering the host cell to produce viral proteins, with the exception of retroviruses. A distinguishing feature of retroviruses is reverse transcription, where the +ssRNA genome serves as a template to synthesize a double-stranded DNA copy that subsequently integrates into the host genome. As retroviral RNAs are produced by the host cell transcriptional machinery and are largely indistinguishable from cellular mRNAs, we investigated the potential of incoming retroviral genomes to directly express proteins. Here we show through multiple, complementary methods that retroviral genomes are translated after entry. Our findings challenge the notion that retroviruses require reverse transcription to produce viral proteins. Synthesis of retroviral proteins in the absence of productive infection has significant implications for basic retrovirology, immune responses and gene therapy applications.


Assuntos
RNA , Retroviridae , Retroviridae/genética , Terapia Genética , RNA Mensageiro/genética , Proteínas Virais
18.
Rev Med Virol ; 34(1): e2486, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37905387

RESUMO

As an important and serious condition impacting human health, the diagnosis, and treatment of tumours is clinically vital because tumour cell immune escape sustains tumour development. Programed death ligand-1 (PD-L1) on tumour cell surfaces binds to the programed death-1 (PD-1), inhibits T cell activation, and induces apoptosis, and incapacitates cells. This allows tumour cells to evade recognition and clearance by the immune system, thereby permitting tumour occurrence, and development and poor prognosis outcomes in patients with tumours. Currently, anti-PD-1/PD-L1 immunotherapy has become pivotal in tumour treatment. Pathogens, especially viruses, are important factors which induce many tumours. In this article, we examine associations between Epstein-Barr virus, human papilloma virus, hepatitis B virus, hepatitis C virus, and human immunodeficiency virus type 1-related tumours and PD-1/PD-L1 axis.


Assuntos
Infecções por Vírus Epstein-Barr , Neoplasias , Humanos , Herpesvirus Humano 4 , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Ligantes , Neoplasias/terapia
19.
J Wildl Dis ; 60(1): 139-150, 2024 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-37972643

RESUMO

Lymphoproliferative disease virus (LPDV) and reticuloendotheliosis virus (REV) are oncogenic retroviruses that can cause disease in wild and domestic fowl. Lymphoproliferative disease virus infections are common and widespread in Wild Turkeys (Meleagris gallopavo) in the US and east-central Canada, while REV has been detected worldwide in numerous avian host species. We tested tissues (spleen, liver, and/or bone marrow, plus neoplastic tissue, if present) from 172 Wild Turkeys that underwent necropsy from December 2018 through October 2021 for both viruses using PCR. We evaluated demographic, geographic, temporal, and seasonal data by chi-square test of independence and logistic regression for turkeys infected with LPDV and/or REV. At least one of these retroviruses was detected in 80.8% (139/172) of Wild Turkeys from 15 US states, with significantly more turkeys being positive for LPDV (72.1%, 124/172) versus REV (43.6%, 75/172; P<0.001). Both viruses (coinfections) were detected in 34.9% (60/172) of turkeys. Among LPDV-infected turkeys (including coinfections), bone marrow had the highest detection rate (38/58, 65.5%), significantly higher than spleen (30/58, 51.7%) and liver (20/58, 34.5%; P<0.001). In REV-infected turkeys, bone marrow had the highest detection rate (24/58, 41.4%). All three tissues (spleen, liver, bone marrow) concurrently tested positive in most (15/25, 60%) REV-infected turkeys. These results suggest LPDV tissue tropism for bone marrow, whereas REV may have broader tissue tropism. Histopathology consistent with lymphoid proliferation and/or neoplasia characteristic of lymphoproliferative disease was evident in 29/172 (16.9%) turkeys assessed, including two REV-only-infected turkeys. Season was significantly associated with LPDV prevalence (highest in winter); year and season were both significantly associated with REV prevalence (highest in 2020 and winter). These data contribute to optimizing diagnostic strategies that may aid in pathogen monitoring and improve detections to increase our understanding of the potential impacts of these viruses on Wild Turkey populations.


Assuntos
Alpharetrovirus , Doenças das Aves , Coinfecção , Vírus da Reticuloendoteliose , Animais , Coinfecção/veterinária , Doenças das Aves/epidemiologia , Retroviridae , Perus
20.
Cell Death Differ ; 31(1): 78-89, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38007552

RESUMO

Cervical cancer is the most common gynecologic cancer, etiologically related to persistent infection of human papillomavirus (HPV). Both the host innate immunity system and the invading HPV have developed sophisticated and effective mechanisms to counteract each other. As a central innate immune sensing signaling adaptor, stimulator of interferon genes (STING) plays a pivotal role in antiviral and antitumor immunity, while viral oncoproteins E7, especially from HPV16/18, are responsible for cell proliferation in cervical cancer, and can inhibit the activity of STING as reported. In this report, we find that activation of STING-TBK1 (TANK-binding kinase 1) promotes the ubiquitin-proteasome degradation of E7 oncoproteins to suppress cervical cancer growth. Mechanistically, TBK1 is able to phosphorylate HPV16/18 E7 oncoproteins at Ser71/Ser78, promoting the ubiquitination and degradation of E7 oncoproteins by E3 ligase HUWE1. Functionally, activated STING inhibits cervical cancer cell proliferation via down-regulating E7 oncoproteins in a TBK1-dependent manner and potentially synergizes with radiation to achieve better effects for antitumor. Furthermore, either genetically or pharmacologically activation of STING-TBK1 suppresses cervical cancer growth in mice, which is independent on its innate immune defense. In conclusion, our findings represent a new layer of the host innate immune defense against oncovirus and provide that activating STING/TBK1 could be a promising strategy to treat patients with HPV-positive cervical cancer.


Assuntos
Proteínas Oncogênicas Virais , Infecções por Papillomavirus , Neoplasias do Colo do Útero , Humanos , Feminino , Animais , Camundongos , Papillomavirus Humano 16/genética , Papillomavirus Humano 16/metabolismo , Neoplasias do Colo do Útero/patologia , Papillomavirus Humano 18/metabolismo , Proteínas Oncogênicas Virais/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo
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