Pub Date : 2024-07-24DOI: 10.3389/fviro.2024.1433931
Kimberly VanderWaal, Nakarin Pamornchainavakul, Mariana Kikuti, Daniel C. Linhares, Giovani Trevisan, Jianqiang Zhang, Tavis K. Anderson, Michael Zeller, Stephanie Rossow, Derald Holtkamp, Dennis N. Makau, Cesar A. Corzo, Igor Paploski
Disease management and epidemiological investigations of porcine reproductive and respiratory syndrome virus-type 2 (PRRSV-2) often rely on grouping together highly related sequences. In the USA, the last five years have seen a major shift within the swine industry when classifying PRRSV-2, beginning to move away from RFLP (restriction fragment length polymorphisms)-typing and adopting the use of phylogenetic lineage-based classification. However, lineages and sub-lineages are large and genetically diverse, making them insufficient for identifying new and emerging variants. Thus, within the lineage system, a dynamic fine-scale classification scheme is needed to provide better resolution on the relatedness of PRRSV-2 viruses to inform disease management and monitoring efforts and facilitate research and communication surrounding circulating PRRSV viruses. Here, we compare fine-scale systems for classifying PRRSV-2 variants (i.e., genetic clusters of closely related ORF5 sequences at finer scales than sub-lineage) using a database of 28,730 sequences from 2010 to 2021, representing >55% of the U.S. pig population. In total, we compared 140 approaches that differed in their tree-building method, criteria, and thresholds for defining variants within phylogenetic trees. Three approaches resulted in variant classifications that were reproducible and robust even when the input data or input phylogenies were changed. For these approaches, the average genetic distance among sequences belonging to the same variant was 2.1–2.5%, and the genetic divergence between variants was 2.5–2.7%. Machine learning classification algorithms were trained to assign new sequences to an existing variant with >95% accuracy, which shows that newly generated sequences can be assigned to a variant without repeating the phylogenetic and clustering analyses. Finally, we identified 73 sequence-clusters (dated <1 year apart with close phylogenetic relatedness) associated with circulation events on single farms. The percent of farm sequence-clusters with an ID change was 6.5–8.7% for our approaches. In contrast, ~43% of farm sequence-clusters had variation in their RFLP-type, further demonstrating how our proposed fine-scale classification system addresses shortcomings of RFLP-typing. Through identifying robust and reproducible classification approaches for PRRSV-2, this work lays the foundation for a fine-scale system that would more reliably group related field viruses and provide better resolution for decision-making surrounding disease management.
{"title":"Frontiers | Phylogenetic-based methods for fine-scale classification of PRRSV-2 ORF5 sequences: a comparison of their robustness and reproducibility","authors":"Kimberly VanderWaal, Nakarin Pamornchainavakul, Mariana Kikuti, Daniel C. Linhares, Giovani Trevisan, Jianqiang Zhang, Tavis K. Anderson, Michael Zeller, Stephanie Rossow, Derald Holtkamp, Dennis N. Makau, Cesar A. Corzo, Igor Paploski","doi":"10.3389/fviro.2024.1433931","DOIUrl":"https://doi.org/10.3389/fviro.2024.1433931","url":null,"abstract":"Disease management and epidemiological investigations of porcine reproductive and respiratory syndrome virus-type 2 (PRRSV-2) often rely on grouping together highly related sequences. In the USA, the last five years have seen a major shift within the swine industry when classifying PRRSV-2, beginning to move away from RFLP (restriction fragment length polymorphisms)-typing and adopting the use of phylogenetic lineage-based classification. However, lineages and sub-lineages are large and genetically diverse, making them insufficient for identifying new and emerging variants. Thus, within the lineage system, a dynamic fine-scale classification scheme is needed to provide better resolution on the relatedness of PRRSV-2 viruses to inform disease management and monitoring efforts and facilitate research and communication surrounding circulating PRRSV viruses. Here, we compare fine-scale systems for classifying PRRSV-2 variants (i.e., genetic clusters of closely related ORF5 sequences at finer scales than sub-lineage) using a database of 28,730 sequences from 2010 to 2021, representing >55% of the U.S. pig population. In total, we compared 140 approaches that differed in their tree-building method, criteria, and thresholds for defining variants within phylogenetic trees. Three approaches resulted in variant classifications that were reproducible and robust even when the input data or input phylogenies were changed. For these approaches, the average genetic distance among sequences belonging to the same variant was 2.1–2.5%, and the genetic divergence between variants was 2.5–2.7%. Machine learning classification algorithms were trained to assign new sequences to an existing variant with >95% accuracy, which shows that newly generated sequences can be assigned to a variant without repeating the phylogenetic and clustering analyses. Finally, we identified 73 sequence-clusters (dated <1 year apart with close phylogenetic relatedness) associated with circulation events on single farms. The percent of farm sequence-clusters with an ID change was 6.5–8.7% for our approaches. In contrast, ~43% of farm sequence-clusters had variation in their RFLP-type, further demonstrating how our proposed fine-scale classification system addresses shortcomings of RFLP-typing. Through identifying robust and reproducible classification approaches for PRRSV-2, this work lays the foundation for a fine-scale system that would more reliably group related field viruses and provide better resolution for decision-making surrounding disease management.","PeriodicalId":73114,"journal":{"name":"Frontiers in virology","volume":"12 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142193102","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-17DOI: 10.3389/fviro.2024.1422934
Zachary Lozier, Lilyahna Hill, Elizabeth Semmann, W. Allen Miller
Tombusviridae is a large family of single-stranded, positive-sense RNA plant viruses with uncapped, non-polyadenylated genomes encoding 4–7 open reading frames (ORFs). Previously, we discovered, by high-throughput sequencing of maize and teosinte RNA, a novel genome of a virus we call Maize-associated tombusvirus (MaTV). Here we determined the precise termini of the MaTV genome by using 5’ and 3’ rapid amplification of cDNA ends (RACE). In GenBank, we discovered eleven other nearly complete viral genomes with MaTV-like genome organizations and related RNA-dependent RNA polymerase (RdRp) sequences. These genomes came from diverse plant, fungal, invertebrate and vertebrate organisms, and some have been found in multiple organisms across the globe. The available 5’ untranslated regions (UTRs) of these genomes are remarkably long: at least 438 to 727 nucleotides (nt), in contrast to those of other tombusvirids, which are <150 nt. Moreover these UTRs contain 6 to 12 AUG triplets that are unlikely to be start codons, because - with the possible exception of MaTV - there are no large or conserved ORFs in the 5’ UTRs. Such features suggest an internal ribosome entry site (IRES), but the only conserved features we found were that the 50 nt upstream of and adjacent to the ORF1 start codon are cytosine-rich and guanosine-poor. ORF2 (RdRp gene) appears to be translated by in-frame ribosomal readthrough of the ORF1 stop codon. In all twelve genomes we identified RNA structures known in other tombusvirids to facilitate this readthrough. ORF4 overlaps with ORF3 (coat protein gene) and may initiate with a non-AUG start codon. ORF5 is predicted to be translated by readthrough of the ORF3 stop codon. The proteins encoded by ORFs 4 and 5 diverge highly from each other and from those of the similarly organized luteo- and poleroviruses. We also found no obvious 3’ cap-independent translation elements, which are present in other tombusvirids. The twelve genomes diverge sufficiently from other tombusvirids to warrant classification in a new genus. Because they contain two leaky stop codons and a potential leaky start codon, we propose to name this genus Rimosavirus (rimosa = leaky in Latin).
{"title":"Frontiers | A proposed new Tombusviridae genus featuring extremely long 5' untranslated regions and a luteo/polerovirus-like gene block","authors":"Zachary Lozier, Lilyahna Hill, Elizabeth Semmann, W. Allen Miller","doi":"10.3389/fviro.2024.1422934","DOIUrl":"https://doi.org/10.3389/fviro.2024.1422934","url":null,"abstract":"Tombusviridae is a large family of single-stranded, positive-sense RNA plant viruses with uncapped, non-polyadenylated genomes encoding 4–7 open reading frames (ORFs). Previously, we discovered, by high-throughput sequencing of maize and teosinte RNA, a novel genome of a virus we call Maize-associated tombusvirus (MaTV). Here we determined the precise termini of the MaTV genome by using 5’ and 3’ rapid amplification of cDNA ends (RACE). In GenBank, we discovered eleven other nearly complete viral genomes with MaTV-like genome organizations and related RNA-dependent RNA polymerase (RdRp) sequences. These genomes came from diverse plant, fungal, invertebrate and vertebrate organisms, and some have been found in multiple organisms across the globe. The available 5’ untranslated regions (UTRs) of these genomes are remarkably long: at least 438 to 727 nucleotides (nt), in contrast to those of other tombusvirids, which are <150 nt. Moreover these UTRs contain 6 to 12 AUG triplets that are unlikely to be start codons, because - with the possible exception of MaTV - there are no large or conserved ORFs in the 5’ UTRs. Such features suggest an internal ribosome entry site (IRES), but the only conserved features we found were that the 50 nt upstream of and adjacent to the ORF1 start codon are cytosine-rich and guanosine-poor. ORF2 (RdRp gene) appears to be translated by in-frame ribosomal readthrough of the ORF1 stop codon. In all twelve genomes we identified RNA structures known in other tombusvirids to facilitate this readthrough. ORF4 overlaps with ORF3 (coat protein gene) and may initiate with a non-AUG start codon. ORF5 is predicted to be translated by readthrough of the ORF3 stop codon. The proteins encoded by ORFs 4 and 5 diverge highly from each other and from those of the similarly organized luteo- and poleroviruses. We also found no obvious 3’ cap-independent translation elements, which are present in other tombusvirids. The twelve genomes diverge sufficiently from other tombusvirids to warrant classification in a new genus. Because they contain two leaky stop codons and a potential leaky start codon, we propose to name this genus Rimosavirus (rimosa = leaky in Latin).","PeriodicalId":73114,"journal":{"name":"Frontiers in virology","volume":"70 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141944651","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-12DOI: 10.3389/fviro.2024.1429785
Provia Ainembabazi, Letisha Najjemba, Joseph Musaazi, Mario Hönemann, Barbara Castelnuovo, Amrei von Braun
A cross-sectional study on severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) seroprevalence among unvaccinated people living with HIV (PLWH) was conducted in Kampala, Uganda, in 2022. Data collection was done using a structured questionnaire. SARS-CoV-2 serologies were done using the Roche Elecsys Anti-SARS-CoV-2 S immunoassay, which assesses the adaptive humoral immune response to the SARS-CoV-2 Spike protein. A total of 575 PLWH (female n=355, 61.7%) with a median age of 49 years (IQR 39-55) were included. SARS-CoV-2 seroprevalence was 93%. The majority had antibody concentration levels ≥ 250 U/ml (n=383, 66.6%). Participants aged >55 years were significantly more likely to have lower antibody concentrations compared to younger participants (p-value < 0.001). A high BMI (≥ 30 kg/m2) was significantly associated with higher antibody concentrations (p-value 0.001). Concerning COVID-19 history, a small proportion of participants (n=79, 13.6%) reported contact with a known COVID-19 patient. Only 8.1% (n=47) had ever had a nasopharyngeal swab for SARS-CoV-2 RT-PCR done, and 3.1% (n=18) actually had a laboratory-confirmed SARS-CoV-2 infection in the past. SARS-CoV-2 seroprevalence was high among our study population, which may be attributed to the fact that the study took place right after all restrictions were lifted and the population was exposed to the dominant Omicron variant. Interestingly, only a small proportion of infections had been laboratory-confirmed.
{"title":"Frontiers | Severe Acute Respiratory Syndrome Coronavirus-2 seroprevalence in non-vaccinated People Living with HIV in Uganda during the year 2022","authors":"Provia Ainembabazi, Letisha Najjemba, Joseph Musaazi, Mario Hönemann, Barbara Castelnuovo, Amrei von Braun","doi":"10.3389/fviro.2024.1429785","DOIUrl":"https://doi.org/10.3389/fviro.2024.1429785","url":null,"abstract":"A cross-sectional study on severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) seroprevalence among unvaccinated people living with HIV (PLWH) was conducted in Kampala, Uganda, in 2022. Data collection was done using a structured questionnaire. SARS-CoV-2 serologies were done using the Roche Elecsys Anti-SARS-CoV-2 S immunoassay, which assesses the adaptive humoral immune response to the SARS-CoV-2 Spike protein. A total of 575 PLWH (female n=355, 61.7%) with a median age of 49 years (IQR 39-55) were included. SARS-CoV-2 seroprevalence was 93%. The majority had antibody concentration levels ≥ 250 U/ml (n=383, 66.6%). Participants aged >55 years were significantly more likely to have lower antibody concentrations compared to younger participants (p-value < 0.001). A high BMI (≥ 30 kg/m2) was significantly associated with higher antibody concentrations (p-value 0.001). Concerning COVID-19 history, a small proportion of participants (n=79, 13.6%) reported contact with a known COVID-19 patient. Only 8.1% (n=47) had ever had a nasopharyngeal swab for SARS-CoV-2 RT-PCR done, and 3.1% (n=18) actually had a laboratory-confirmed SARS-CoV-2 infection in the past. SARS-CoV-2 seroprevalence was high among our study population, which may be attributed to the fact that the study took place right after all restrictions were lifted and the population was exposed to the dominant Omicron variant. Interestingly, only a small proportion of infections had been laboratory-confirmed.","PeriodicalId":73114,"journal":{"name":"Frontiers in virology","volume":"78 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141944525","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-20DOI: 10.3389/fviro.2024.1419276
Shirish Yasa, Sayal Guirales-Medrano, Denis Jacob Machado, Colby Ford, Dan Janies
The emergence of SARS-CoV-2 lineages derived from Omicron, including BA.2.86 (nicknamed “Pirola”) and its relative, JN.1, has raised concerns about their potential impact on public and personal health due to numerous novel mutations. Despite this, predicting their implications based solely on mutation counts proves challenging. Empirical evidence of JN.1’s increased immune evasion capacity in relation to previous variants is mixed. To improve predictions beyond what is possible based solely on mutation counts, we conducted extensive in silico analyses on the binding affinity between the RBD of different SARS-CoV-2 variants (Wuhan-Hu-1, BA.1/B.1.1.529, BA.2, XBB.1.5, BA.2.86, and JN.1) and neutralizing antibodies from vaccinated or infected individuals, as well as the human angiotensin-converting enzyme 2 (ACE2) receptor. We observed no statistically significant difference in binding affinity between BA.2.86 or JN.1 and other variants. Therefore, we conclude that the new SARS-CoV-2 variants have no pronounced immune escape or infection capacity compared to previous variants. However, minor reductions in binding affinity for both the antibodies and ACE2 were noted for JN.1. Future research in this area will benefit from increased structural analyses of memory B-cell derived antibodies and should emphasize the importance of choosing appropriate samples for in silico studies to assess protection provided by vaccination and infection. Moreover, the fitness benefits of genomic variation outside of the RBD of BA.2.86 and JN.1 need to be investigated. This research contributes to understanding the BA.2.86 and JN.1 variants’ potential impact on public health.
{"title":"Frontiers | Predicting Antibody and ACE2 Affinity for SARS-CoV-2 BA.2.86 and JN.1 with In Silico Protein Modeling and Docking","authors":"Shirish Yasa, Sayal Guirales-Medrano, Denis Jacob Machado, Colby Ford, Dan Janies","doi":"10.3389/fviro.2024.1419276","DOIUrl":"https://doi.org/10.3389/fviro.2024.1419276","url":null,"abstract":"The emergence of SARS-CoV-2 lineages derived from Omicron, including BA.2.86 (nicknamed “Pirola”) and its relative, JN.1, has raised concerns about their potential impact on public and personal health due to numerous novel mutations. Despite this, predicting their implications based solely on mutation counts proves challenging. Empirical evidence of JN.1’s increased immune evasion capacity in relation to previous variants is mixed. To improve predictions beyond what is possible based solely on mutation counts, we conducted extensive in silico analyses on the binding affinity between the RBD of different SARS-CoV-2 variants (Wuhan-Hu-1, BA.1/B.1.1.529, BA.2, XBB.1.5, BA.2.86, and JN.1) and neutralizing antibodies from vaccinated or infected individuals, as well as the human angiotensin-converting enzyme 2 (ACE2) receptor. We observed no statistically significant difference in binding affinity between BA.2.86 or JN.1 and other variants. Therefore, we conclude that the new SARS-CoV-2 variants have no pronounced immune escape or infection capacity compared to previous variants. However, minor reductions in binding affinity for both the antibodies and ACE2 were noted for JN.1. Future research in this area will benefit from increased structural analyses of memory B-cell derived antibodies and should emphasize the importance of choosing appropriate samples for in silico studies to assess protection provided by vaccination and infection. Moreover, the fitness benefits of genomic variation outside of the RBD of BA.2.86 and JN.1 need to be investigated. This research contributes to understanding the BA.2.86 and JN.1 variants’ potential impact on public health.","PeriodicalId":73114,"journal":{"name":"Frontiers in virology","volume":"32 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141741940","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-21DOI: 10.3389/fviro.2024.1393475
Deelan S. Doolabh, Philippe Selhorst, Carolyn Williamson, Denis Chopera, Melissa-Rose Abrahams
IntroductionElucidation of mechanisms that drive HIV latency is essential to identifying cure strategies. While host mechanisms associated with viral persistence on antiretroviral therapy (ART) have been well studied, less is known about the viral properties that influence latency. The viral promoter element, the 5’ long terminal repeat (LTR), has been shown to affect the number of latently infected cells shortly after infection. Here we investigated the role of subtype C LTR genotypic variation on the establishment of latency in a dual reporter HIV-1 infection model.MethodsThe LTR U3 and R regions from 11 women with acute/early subtype C HIV infection were cloned into the dual reporter pRGH plasmid. Latency potential was calculated based on the expression of fluorescent reporter genes in Jurkat E6–1 cells measured by flow cytometry as the proportion of latent (mCherry +ve cells)/proportion of active (eGFP +ve mCherry +ve cells) infection. Reversal of latency was performed using PMA/Ionomycin stimulation 24 hours before fixing of cells. LTR transcriptional capacity, in the presence and absence of a heterologous subtype C Tat, was measured for the same LTRs cloned into a pGL4.10 luciferase expression vector following transfection of HEK293T cells.ResultsThe majority of proviruses were latent at day 8 post-infection, yet the proportion of latently infected cells varied significantly across participants. We observed a median latent:active infection ratio of 1.79 (range 0.86–2.83) across LTRs with the hierarchy of latency potential remaining consistent across repeat experiments. The median latent:active infection ratio decreased by a median of 3-fold following PMA/Ionomycin stimulation to 0.55 (range 0.46–0.78) indicating that a proportion of latently infected cells could produce viral proteins upon activation. Latency potential did not correlate with LTR transcriptional capacity.ConclusionsWe found intra-subtype level differences in the latency potential of LTRs from South African women independent of their transcriptional capacity, suggesting that HIV-1 LTRs have intrinsic properties that influence the proportion of latently infected cells shortly after infection. The inability to reactivate viral expression in all latently infected cells supports the complex nature of mechanisms driving latency and the need for continued advancements in methods used to study these mechanisms.
{"title":"Frontiers | HIV latency potential may beis influenced by intra-subtype genetic differences in the viral long-terminal repeat","authors":"Deelan S. Doolabh, Philippe Selhorst, Carolyn Williamson, Denis Chopera, Melissa-Rose Abrahams","doi":"10.3389/fviro.2024.1393475","DOIUrl":"https://doi.org/10.3389/fviro.2024.1393475","url":null,"abstract":"IntroductionElucidation of mechanisms that drive HIV latency is essential to identifying cure strategies. While host mechanisms associated with viral persistence on antiretroviral therapy (ART) have been well studied, less is known about the viral properties that influence latency. The viral promoter element, the 5’ long terminal repeat (LTR), has been shown to affect the number of latently infected cells shortly after infection. Here we investigated the role of subtype C LTR genotypic variation on the establishment of latency in a dual reporter HIV-1 infection model.MethodsThe LTR U3 and R regions from 11 women with acute/early subtype C HIV infection were cloned into the dual reporter pRGH plasmid. Latency potential was calculated based on the expression of fluorescent reporter genes in Jurkat E6–1 cells measured by flow cytometry as the proportion of latent (mCherry +ve cells)/proportion of active (eGFP +ve mCherry +ve cells) infection. Reversal of latency was performed using PMA/Ionomycin stimulation 24 hours before fixing of cells. LTR transcriptional capacity, in the presence and absence of a heterologous subtype C Tat, was measured for the same LTRs cloned into a pGL4.10 luciferase expression vector following transfection of HEK293T cells.ResultsThe majority of proviruses were latent at day 8 post-infection, yet the proportion of latently infected cells varied significantly across participants. We observed a median latent:active infection ratio of 1.79 (range 0.86–2.83) across LTRs with the hierarchy of latency potential remaining consistent across repeat experiments. The median latent:active infection ratio decreased by a median of 3-fold following PMA/Ionomycin stimulation to 0.55 (range 0.46–0.78) indicating that a proportion of latently infected cells could produce viral proteins upon activation. Latency potential did not correlate with LTR transcriptional capacity.ConclusionsWe found intra-subtype level differences in the latency potential of LTRs from South African women independent of their transcriptional capacity, suggesting that HIV-1 LTRs have intrinsic properties that influence the proportion of latently infected cells shortly after infection. The inability to reactivate viral expression in all latently infected cells supports the complex nature of mechanisms driving latency and the need for continued advancements in methods used to study these mechanisms.","PeriodicalId":73114,"journal":{"name":"Frontiers in virology","volume":"19 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141530203","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-15DOI: 10.3389/fviro.2024.1386580
Rohini A. Nangare, Virendra Gajbhiye, Yogesh A. Karpe
Chikungunya virus (CHIKV) is a vector-born alphavirus responsible for chikungunya fever with clinical manifestation of polyarthritis transmitted by Aedes aegypti and Aedes albopictus. Establishing viral pathogenesis needs host machinery modulation, and the microRNAs (miRNA) modulate host cellular machinery to establish the infection or inhibit viral replication. miRNAs are the small noncoding RNA that control the gene expression. They are essential in cell differentiation, growth, development, and apoptosis. It also affects disease progression, cancer, and viral infection. CHIKV infection causes differential expression of miRNA, and miRNA has target genes involved in different cellular functions. These target genes may be crucial in CHIKV replication and cell growth. Suppression or overexpression of these miRNAs may have been linked with CHIKV pathogenesis by regulating immune and signaling pathways. Identification of biomarkers in disease progression through the study of circulating miRNAs during CHIKV infection is an emerging field. Therefore, understanding miRNAs’ differential expression and function during CHIKV infection is essential. The detailed studies on the miRNA-mediated regulatory network will provide new ways to develop miRNA-based therapies.
{"title":"Role of miRNAs in the Chikungunya virus replication and pathogenesis","authors":"Rohini A. Nangare, Virendra Gajbhiye, Yogesh A. Karpe","doi":"10.3389/fviro.2024.1386580","DOIUrl":"https://doi.org/10.3389/fviro.2024.1386580","url":null,"abstract":"Chikungunya virus (CHIKV) is a vector-born alphavirus responsible for chikungunya fever with clinical manifestation of polyarthritis transmitted by Aedes aegypti and Aedes albopictus. Establishing viral pathogenesis needs host machinery modulation, and the microRNAs (miRNA) modulate host cellular machinery to establish the infection or inhibit viral replication. miRNAs are the small noncoding RNA that control the gene expression. They are essential in cell differentiation, growth, development, and apoptosis. It also affects disease progression, cancer, and viral infection. CHIKV infection causes differential expression of miRNA, and miRNA has target genes involved in different cellular functions. These target genes may be crucial in CHIKV replication and cell growth. Suppression or overexpression of these miRNAs may have been linked with CHIKV pathogenesis by regulating immune and signaling pathways. Identification of biomarkers in disease progression through the study of circulating miRNAs during CHIKV infection is an emerging field. Therefore, understanding miRNAs’ differential expression and function during CHIKV infection is essential. The detailed studies on the miRNA-mediated regulatory network will provide new ways to develop miRNA-based therapies.","PeriodicalId":73114,"journal":{"name":"Frontiers in virology","volume":"29 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141258102","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-22DOI: 10.3389/fviro.2024.1410258
Nicholas Saladino, Daniel J. Salamango
Viruses are obligate intracellular pathogens that hijack a myriad of host cell processes to facilitate replication and suppress host antiviral defenses. In its essence, a virus is a segment of foreign nucleic acid that engages host cell machinery to drive viral genome replication, gene transcription, and protein synthesis to generate progeny virions. Because of this, host organisms have developed sophisticated detection systems that activate antiviral defenses following recognition of aberrant nucleic acids. For example, recognition of viral nucleic acids by host DNA repair proteins results in compromised viral genome integrity, induction of antiviral inflammatory programs, cell cycle arrest, and apoptosis. Unsurprisingly, diverse viral families have evolved multiple strategies that fine-tune host DNA repair responses to suppress activation of antiviral defenses while simultaneously hijacking DNA repair proteins to facilitate virus replication. This review summarizes common molecular strategies viruses deploy to exploit host DNA repair mechanisms.
病毒是一种强制性细胞内病原体，它劫持宿主细胞的无数过程，以促进复制和抑制宿主的抗病毒防御。从本质上讲，病毒是一段外来核酸，它与宿主细胞机制结合，驱动病毒基因组复制、基因转录和蛋白质合成，从而产生后代病毒。正因为如此，宿主生物已经开发出复杂的检测系统，在识别到异常核酸后启动抗病毒防御系统。例如，宿主 DNA 修复蛋白对病毒核酸的识别会导致病毒基因组完整性受损、诱发抗病毒炎症程序、细胞周期停滞和细胞凋亡。毫不奇怪，各种病毒家族已经进化出多种策略，对宿主 DNA 修复反应进行微调，以抑制抗病毒防御系统的激活，同时劫持 DNA 修复蛋白以促进病毒复制。本综述总结了病毒利用宿主 DNA 修复机制的常见分子策略。
{"title":"Wielding a double-edged sword: viruses exploit host DNA repair systems to facilitate replication while bypassing immune activation","authors":"Nicholas Saladino, Daniel J. Salamango","doi":"10.3389/fviro.2024.1410258","DOIUrl":"https://doi.org/10.3389/fviro.2024.1410258","url":null,"abstract":"Viruses are obligate intracellular pathogens that hijack a myriad of host cell processes to facilitate replication and suppress host antiviral defenses. In its essence, a virus is a segment of foreign nucleic acid that engages host cell machinery to drive viral genome replication, gene transcription, and protein synthesis to generate progeny virions. Because of this, host organisms have developed sophisticated detection systems that activate antiviral defenses following recognition of aberrant nucleic acids. For example, recognition of viral nucleic acids by host DNA repair proteins results in compromised viral genome integrity, induction of antiviral inflammatory programs, cell cycle arrest, and apoptosis. Unsurprisingly, diverse viral families have evolved multiple strategies that fine-tune host DNA repair responses to suppress activation of antiviral defenses while simultaneously hijacking DNA repair proteins to facilitate virus replication. This review summarizes common molecular strategies viruses deploy to exploit host DNA repair mechanisms.","PeriodicalId":73114,"journal":{"name":"Frontiers in virology","volume":"3 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140841166","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-15DOI: 10.3389/fviro.2024.1380030
Chandrav De, Raymond J. Pickles, Wenbo Yao, Baolin Liao, Allison Boone, Rachel A. Cleary, J. Victor Garcia, Angela Wahl
Respiratory syncytial virus (RSV) is a substantial cause of severe lower respiratory tract infections in infants, young children, older adults, and immunocompromised individuals. There is a vital need for effective therapeutics to prevent and/or treat severe RSV infection in these high-risk individuals. The development and pre-clinical testing of candidate RSV therapeutics could be accelerated by their evaluation in animal models that recapitulate bronchiolitis and bronchopneumonia, both hallmark features of severe RSV infection in humans. Previously, we demonstrated that implanted human lung tissue in humanized lung-only mice (LoM) can be infected with RSV, resulting in sustained virus replication. Here we analyzed RSV-associated human lung pathology in the human lung implants of RSV-infected LoM. RSV-infected epithelial cells lining the airway and the alveolar regions of human lung implants result in hallmark histological features of RSV bronchiolitis and bronchopneumonia, including distal airway and alveolar lumens clogged with (1) sloughed and necrotic RSV-infected epithelial cells, (2) neutrophil-containing inflammatory infiltrates, and (3) MUC5B-dominated mucus secretions. We also show that treatment of LoM with a small molecule antiviral (ribavirin) or a neutralizing antibody (palivizumab) significantly suppressed and/or prevented RSV infection in vivo. Our data together show that RSV infection of human lung implants in vivo exhibits appropriate cellular tropism and results in the hallmark pathological characteristics of severe bronchiolitis and bronchopneumonia in humans. They also offer proof-of-principle of the utility of this model to evaluate novel approaches for the prevention/treatment of RSV infection.
{"title":"RSV infection of humanized lung-only mice induces pathological changes resembling severe bronchiolitis and bronchopneumonia","authors":"Chandrav De, Raymond J. Pickles, Wenbo Yao, Baolin Liao, Allison Boone, Rachel A. Cleary, J. Victor Garcia, Angela Wahl","doi":"10.3389/fviro.2024.1380030","DOIUrl":"https://doi.org/10.3389/fviro.2024.1380030","url":null,"abstract":"Respiratory syncytial virus (RSV) is a substantial cause of severe lower respiratory tract infections in infants, young children, older adults, and immunocompromised individuals. There is a vital need for effective therapeutics to prevent and/or treat severe RSV infection in these high-risk individuals. The development and pre-clinical testing of candidate RSV therapeutics could be accelerated by their evaluation in animal models that recapitulate bronchiolitis and bronchopneumonia, both hallmark features of severe RSV infection in humans. Previously, we demonstrated that implanted human lung tissue in humanized lung-only mice (LoM) can be infected with RSV, resulting in sustained virus replication. Here we analyzed RSV-associated human lung pathology in the human lung implants of RSV-infected LoM. RSV-infected epithelial cells lining the airway and the alveolar regions of human lung implants result in hallmark histological features of RSV bronchiolitis and bronchopneumonia, including distal airway and alveolar lumens clogged with (1) sloughed and necrotic RSV-infected epithelial cells, (2) neutrophil-containing inflammatory infiltrates, and (3) MUC5B-dominated mucus secretions. We also show that treatment of LoM with a small molecule antiviral (ribavirin) or a neutralizing antibody (palivizumab) significantly suppressed and/or prevented RSV infection in vivo. Our data together show that RSV infection of human lung implants in vivo exhibits appropriate cellular tropism and results in the hallmark pathological characteristics of severe bronchiolitis and bronchopneumonia in humans. They also offer proof-of-principle of the utility of this model to evaluate novel approaches for the prevention/treatment of RSV infection.","PeriodicalId":73114,"journal":{"name":"Frontiers in virology","volume":"54 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140888614","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-09DOI: 10.3389/fviro.2024.1289258
Edith Koskei, Solomon Langat, James Mutisya, Francis Mulwa, Joel Lutomiah, Hellen Koka, Samuel O. Oyola, Rebecca Waihenya, Sepha N. Mabeya, Rosemary Sang
BackgroundUntil recently, arbovirus surveillance is mainly focused on mosquito and tick vectors, resulting in the discovery of several mosquito- and tick-borne arboviruses. However, the role of sandflies in arbovirus transmission and disease has remained largely unexplored. This study sought to isolate and characterize arboviruses from phlebotomine sandflies from selected pastoral ecozones in the North Rift region of Kenya.MethodsSandflies were collected from selected sites in North Rift Kenya between 2015 and 2018. They were sorted and pooled by sex, site, and collection date. The pools were homogenized and inoculated onto Vero cells for virus isolation. The positive pools were analyzed by polymerase chain reaction targeting different arboviruses. The isolates were further characterized by high-throughput sequencing using Illumina Miseq platform.ResultsApproximately 28,226 sandflies translating to 824 pools were sampled from the selected regions. A total of 11 showed reproducible cytopathic effects on Vero cells. We identified five arboviruses: sindbis (n = 4) from Kacheliba and Baringo, Chandipura (n = 4) from Turkana and Baringo, Koutango (n = 1) and Ntepes (n = 1) from Baringo, and Bogoria (n = 1) from Kacheliba. The percent identities of the identified viruses were approximately 80% to 98% compared to known viruses in GenBank, suggesting that some of them could be novel viruses.ConclusionThis study successfully isolated and characterized five arboviruses from sandflies. The findings suggest that sandflies are potential hosts of a wide range of arboviruses and are therefore important vectors to consider in arbovirus surveillance and evaluated for their ability to transmit them. Further studies are needed to determine the public health importance and extent of exposure of these viruses to humans and livestock populations.
{"title":"Isolation and phylogenetic characterization of arboviruses circulating among phlebotomine sandflies in parts of North Rift, Kenya","authors":"Edith Koskei, Solomon Langat, James Mutisya, Francis Mulwa, Joel Lutomiah, Hellen Koka, Samuel O. Oyola, Rebecca Waihenya, Sepha N. Mabeya, Rosemary Sang","doi":"10.3389/fviro.2024.1289258","DOIUrl":"https://doi.org/10.3389/fviro.2024.1289258","url":null,"abstract":"BackgroundUntil recently, arbovirus surveillance is mainly focused on mosquito and tick vectors, resulting in the discovery of several mosquito- and tick-borne arboviruses. However, the role of sandflies in arbovirus transmission and disease has remained largely unexplored. This study sought to isolate and characterize arboviruses from phlebotomine sandflies from selected pastoral ecozones in the North Rift region of Kenya.MethodsSandflies were collected from selected sites in North Rift Kenya between 2015 and 2018. They were sorted and pooled by sex, site, and collection date. The pools were homogenized and inoculated onto Vero cells for virus isolation. The positive pools were analyzed by polymerase chain reaction targeting different arboviruses. The isolates were further characterized by high-throughput sequencing using Illumina Miseq platform.ResultsApproximately 28,226 sandflies translating to 824 pools were sampled from the selected regions. A total of 11 showed reproducible cytopathic effects on Vero cells. We identified five arboviruses: sindbis (n = 4) from Kacheliba and Baringo, Chandipura (n = 4) from Turkana and Baringo, Koutango (n = 1) and Ntepes (n = 1) from Baringo, and Bogoria (n = 1) from Kacheliba. The percent identities of the identified viruses were approximately 80% to 98% compared to known viruses in GenBank, suggesting that some of them could be novel viruses.ConclusionThis study successfully isolated and characterized five arboviruses from sandflies. The findings suggest that sandflies are potential hosts of a wide range of arboviruses and are therefore important vectors to consider in arbovirus surveillance and evaluated for their ability to transmit them. Further studies are needed to determine the public health importance and extent of exposure of these viruses to humans and livestock populations.","PeriodicalId":73114,"journal":{"name":"Frontiers in virology","volume":"45 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140841169","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-08DOI: 10.3389/fviro.2024.1379217
Nelson Sonela, Jaclyn Mann, Celestin Godwe, Oumarou H. Goni, Mérime Tchakoute, Nathalie Nkoue, Tulio de Oliveira, Mark A. Brockman, Zabrina L. Brumme, Thumbi Ndung’u, Marcel Tongo
HIV-1 group M (HIV-1M) lineages downregulate HLA-I and CD4 expression via their Nef proteins. We hypothesized that these Nef functions may be partially responsible for the differences in prevalence of viruses from different lineages that co-circulate within an epidemic. Here, we characterized these two Nef activities in HIV-1M isolates from Cameroon, where multiple variants have been circulating since the pandemic’s origin. Single HIV-1 Nef clones from 234 HIV-1-ART naïve individuals living in remote villages and two cosmopolitan cities of Cameroon, sampled between 2000 and 2013, were isolated from plasma HIV RNA and analyzed for their capacity to downregulate HLA-I and CD4 molecules. We found that, despite a large degree of within- and inter- lineage variation, the ability of Nef to downregulate HLA-I was similar across these different viruses. Moreover, Nef-mediated CD4 downregulation activity was also well conserved across the different lineages found in Cameroon. In addition, we observed a trend towards higher HLA-I downregulation activity of viruses circulating in the cosmopolitan cities versus the remote villages, whereas the CD4 downregulation activities were similar across the two settings. Furthermore, we noted a significant decline of HLA-I downregulation activity from 2000 to 2013, providing additional evidence supporting the attenuation of the global HIV-1M population over time. Finally, we identified 18 amino acids associated with differential HLA-I downregulation and 13 amino acids associated with differential CD4 downregulation within the dominant CRF02_AG lineage. Our lack of observation of HIV lineage-related differences in Nef-mediated HLA-I and CD4 downregulation function suggests that these activities do not substantively influence the prevalence of different HIV-1M lineages in Cameroon.
{"title":"No detectable differences in Nef-mediated downregulation of HLA-I and CD4 molecules among HIV-1 group M lineages circulating in Cameroon, where the pandemic originated","authors":"Nelson Sonela, Jaclyn Mann, Celestin Godwe, Oumarou H. Goni, Mérime Tchakoute, Nathalie Nkoue, Tulio de Oliveira, Mark A. Brockman, Zabrina L. Brumme, Thumbi Ndung’u, Marcel Tongo","doi":"10.3389/fviro.2024.1379217","DOIUrl":"https://doi.org/10.3389/fviro.2024.1379217","url":null,"abstract":"HIV-1 group M (HIV-1M) lineages downregulate HLA-I and CD4 expression via their Nef proteins. We hypothesized that these Nef functions may be partially responsible for the differences in prevalence of viruses from different lineages that co-circulate within an epidemic. Here, we characterized these two Nef activities in HIV-1M isolates from Cameroon, where multiple variants have been circulating since the pandemic’s origin. Single HIV-1 Nef clones from 234 HIV-1-ART naïve individuals living in remote villages and two cosmopolitan cities of Cameroon, sampled between 2000 and 2013, were isolated from plasma HIV RNA and analyzed for their capacity to downregulate HLA-I and CD4 molecules. We found that, despite a large degree of within- and inter- lineage variation, the ability of Nef to downregulate HLA-I was similar across these different viruses. Moreover, Nef-mediated CD4 downregulation activity was also well conserved across the different lineages found in Cameroon. In addition, we observed a trend towards higher HLA-I downregulation activity of viruses circulating in the cosmopolitan cities versus the remote villages, whereas the CD4 downregulation activities were similar across the two settings. Furthermore, we noted a significant decline of HLA-I downregulation activity from 2000 to 2013, providing additional evidence supporting the attenuation of the global HIV-1M population over time. Finally, we identified 18 amino acids associated with differential HLA-I downregulation and 13 amino acids associated with differential CD4 downregulation within the dominant CRF02_AG lineage. Our lack of observation of HIV lineage-related differences in Nef-mediated HLA-I and CD4 downregulation function suggests that these activities do not substantively influence the prevalence of different HIV-1M lineages in Cameroon.","PeriodicalId":73114,"journal":{"name":"Frontiers in virology","volume":"41 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141171490","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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