Yanling Liu,Winston T Chu,Syed Qasim Gilani,Daniel B Woodburn,David X Liu,Akhil A Vinithakumari,Nejra Isic,Amber Boshinski,Donna L Perry,Amanda Hischack,Jeffrey Solomon,Ian Crozier,C Paul Morris
The liver is a key target of pathogenic orthomarburgviruses and orthoebolaviruses, with injury common in severe filovirid disease, yet high-resolution histopathologic quantification is lacking. We addressed this by deploying deep learning (DL) models for pixel-level quantitative analysis of digitized liver pathology slides in lethal rhesus monkey (RM) models of Marburg virus (MARV) and two Ebola virus (EBOV) variants, Makona and Kikwit. Our DL model segmented arteries, veins, bile ducts, and hepatic necrosis, achieving interobserver variability in necrosis segmentation comparable to three pathologists. DL-quantified liver necrosis correlated with exposure virus (f=6.61, p=.006) and was highest in MARV-exposed RMs (11.0%). While filovirid-exposed RMs showed elevations in aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyltransferase (GGT), and alkaline phosphatase (ALP), only ALT levels correlated with necrosis severity. Necrosis localization differed: portal tract-proximate after MARV exposure and central vein-proximate after EBOV exposure. This proof-of-concept work enables future large-scale retrospective "meta-pathologic" analyses.
{"title":"Machine learning-enabled quantification of hepatocellular necrosis in the liver after lethal Marburg and Ebola virus exposures.","authors":"Yanling Liu,Winston T Chu,Syed Qasim Gilani,Daniel B Woodburn,David X Liu,Akhil A Vinithakumari,Nejra Isic,Amber Boshinski,Donna L Perry,Amanda Hischack,Jeffrey Solomon,Ian Crozier,C Paul Morris","doi":"10.1093/infdis/jiag040","DOIUrl":"https://doi.org/10.1093/infdis/jiag040","url":null,"abstract":"The liver is a key target of pathogenic orthomarburgviruses and orthoebolaviruses, with injury common in severe filovirid disease, yet high-resolution histopathologic quantification is lacking. We addressed this by deploying deep learning (DL) models for pixel-level quantitative analysis of digitized liver pathology slides in lethal rhesus monkey (RM) models of Marburg virus (MARV) and two Ebola virus (EBOV) variants, Makona and Kikwit. Our DL model segmented arteries, veins, bile ducts, and hepatic necrosis, achieving interobserver variability in necrosis segmentation comparable to three pathologists. DL-quantified liver necrosis correlated with exposure virus (f=6.61, p=.006) and was highest in MARV-exposed RMs (11.0%). While filovirid-exposed RMs showed elevations in aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyltransferase (GGT), and alkaline phosphatase (ALP), only ALT levels correlated with necrosis severity. Necrosis localization differed: portal tract-proximate after MARV exposure and central vein-proximate after EBOV exposure. This proof-of-concept work enables future large-scale retrospective \"meta-pathologic\" analyses.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"101 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146015185","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}
{"title":"When Time Is of the Essence: Hepatitis C Virus RNA Point-of-Care Testing in 15 Minutes Becomes a Reality.","authors":"Tanya L Applegate,Jason Grebely","doi":"10.1093/infdis/jiaf652","DOIUrl":"https://doi.org/10.1093/infdis/jiaf652","url":null,"abstract":"","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"30 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146015269","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}
BACKGROUNDDespite advances in anthelmintic therapy, there are currently no effective treatments for schistosomiasis-induced liver fibrosis. Previous studies have reported elevated marginal zone B and B1 cell specific protein (MZB1) expression in fibrotic diseases, but its function remains unclear, and its role in schistosomiasis has not been investigated. This study aimed to explore the function and mechanism of MZB1 in Schistosoma japonicum infection.METHODSWe evaluated the expression of Mzb1 in the liver and spleen of Schistosoma-infected mice using methods such as Western blot, qPCR, and immunohistochemistry. We also employed adeno-associated virus (AAV) to knock down Mzb1 gene expression, assessing the role of Mzb1 in the progression of schistosomiasis and its downstream pathways. Additionally, in vivo experiments were conducted using downstream endoplasmic reticulum stress agonists and inhibitors to evaluate the role of this pathway in the progression of schistosomiasis.RESULTSOur findings demonstrated that Mzb1 was significantly upregulated in the liver and spleen tissues of infected mice. Knockdown of Mzb1 markedly reduced liver fibrosis and splenomegaly. Mzb1 was predominantly expressed in CD20-positive B cells and was found to activate endoplasmic reticulum (ER) stress. Inhibition of ER stress alleviated liver fibrosis and splenomegaly, while activation of ER stress exacerbated these pathological conditions and reversed the protective effects of Mzb1 knockdown.CONCLUSIONSWe identified Mzb1 as a key factor that promotes liver fibrosis and splenomegaly in schistosomiasis through the activation of ER stress. This novel pathogenic mechanism may provide a potential therapeutic target for the treatment of schistosomiasis-induced liver fibrosis.
{"title":"Mzb1 Promotes Progression of Schistosomiasis by Inducing Endoplasmic Reticulum Stress.","authors":"Lanyue Pan,Hongyan Kong,Dandan Xiang,Guo Li,Zhilin Zeng,Shuaiwen Huang,Xin Xu,Jingjing Li,Jiaquan Huang","doi":"10.1093/infdis/jiaf639","DOIUrl":"https://doi.org/10.1093/infdis/jiaf639","url":null,"abstract":"BACKGROUNDDespite advances in anthelmintic therapy, there are currently no effective treatments for schistosomiasis-induced liver fibrosis. Previous studies have reported elevated marginal zone B and B1 cell specific protein (MZB1) expression in fibrotic diseases, but its function remains unclear, and its role in schistosomiasis has not been investigated. This study aimed to explore the function and mechanism of MZB1 in Schistosoma japonicum infection.METHODSWe evaluated the expression of Mzb1 in the liver and spleen of Schistosoma-infected mice using methods such as Western blot, qPCR, and immunohistochemistry. We also employed adeno-associated virus (AAV) to knock down Mzb1 gene expression, assessing the role of Mzb1 in the progression of schistosomiasis and its downstream pathways. Additionally, in vivo experiments were conducted using downstream endoplasmic reticulum stress agonists and inhibitors to evaluate the role of this pathway in the progression of schistosomiasis.RESULTSOur findings demonstrated that Mzb1 was significantly upregulated in the liver and spleen tissues of infected mice. Knockdown of Mzb1 markedly reduced liver fibrosis and splenomegaly. Mzb1 was predominantly expressed in CD20-positive B cells and was found to activate endoplasmic reticulum (ER) stress. Inhibition of ER stress alleviated liver fibrosis and splenomegaly, while activation of ER stress exacerbated these pathological conditions and reversed the protective effects of Mzb1 knockdown.CONCLUSIONSWe identified Mzb1 as a key factor that promotes liver fibrosis and splenomegaly in schistosomiasis through the activation of ER stress. This novel pathogenic mechanism may provide a potential therapeutic target for the treatment of schistosomiasis-induced liver fibrosis.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"16 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146005027","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}
Sylvia M LaCourse,Jaclyn N Escudero,Wendy E Whatney,Krista N Krish,Arijita Subuddhi,Sara Belauret,Rachel A Pearson,Lisa Marie Cranmer,Jerphason Mecha,Daniel Matemo,Elizabeth Maleche-Obimbo,John Kinuthia,Barbra A Richardson,Grace John-Stewart,Cheryl L Day
BACKGROUNDReduced early life IFN-γ production capacity may limit sensitivity of IFN-γ release assays (IGRAs) to detect M. tuberculosis (Mtb)-specific responses in young children. Measurement of non-interferon-γ (IFN-γ) cytokine responses may improve detection of these responses in children.METHODSPBMCs from HIV-exposed uninfected (cHEU) and HIV-unexposed (cHUU) children in Western Kenya collected between 6-10 weeks, and at 12 and 24 months of age were incubated overnight with Mtb-specific CFP-10/ESAT-6 peptides and staphylococcus enterotoxin B (SEB, positive control). CD4 and CD8 T cell expression of IFN-γ and non-IFN-γ (IL-2, TNF) cytokines was measured by flow cytometry.RESULTSAmong 213 children, 28.6% had CFP-10/ESAT-6 CD4 and/or CD8 responses up to 24 months of age. No children with a positive Mtb-specific response had a reported known TB exposure. More children exhibited Mtb-specific non-IFN-γ+ (IL-2+ and/or TNF+) responses than IFN-γ+ responses (26.3% vs. 10.3%, p<0.001), including 18.3% identified by non-IFN-γ+ responses alone (non-IFN-γ+ alone 18.3% vs. IFN-γ+ alone 2.4%, p <0.001). Proportion of children with Mtb-specific responses were similar regardless of HIV exposure (cHEU 31.5% vs. cHUU 25.5%, p=0.33). At 6-10 weeks of age, children were more likely to have non-IFN-γ+ vs. IFN-γ+ responses to SEB (positive control) (96.3% vs. 77.8%, p=0.004); however, by 24 months of age 100% of children had both IFN-γ+ and non-IFN-γ+ SEB responses.CONCLUSIONMtb-specific CD4/CD8 responses were common among young Kenyan children up to 24 months of age, despite limited reported TB exposures. Non-IFN-γ+ T cell cytokine expression identified more children than IFN-γ+ who would be potentially missed by commercially available IGRAs.
{"title":"Mtb-specific CFP-10/ESAT-6 CD4 and CD8 T cell non-IFN-γ+ responses are common in young Kenyan children despite low reported TB exposure.","authors":"Sylvia M LaCourse,Jaclyn N Escudero,Wendy E Whatney,Krista N Krish,Arijita Subuddhi,Sara Belauret,Rachel A Pearson,Lisa Marie Cranmer,Jerphason Mecha,Daniel Matemo,Elizabeth Maleche-Obimbo,John Kinuthia,Barbra A Richardson,Grace John-Stewart,Cheryl L Day","doi":"10.1093/infdis/jiag039","DOIUrl":"https://doi.org/10.1093/infdis/jiag039","url":null,"abstract":"BACKGROUNDReduced early life IFN-γ production capacity may limit sensitivity of IFN-γ release assays (IGRAs) to detect M. tuberculosis (Mtb)-specific responses in young children. Measurement of non-interferon-γ (IFN-γ) cytokine responses may improve detection of these responses in children.METHODSPBMCs from HIV-exposed uninfected (cHEU) and HIV-unexposed (cHUU) children in Western Kenya collected between 6-10 weeks, and at 12 and 24 months of age were incubated overnight with Mtb-specific CFP-10/ESAT-6 peptides and staphylococcus enterotoxin B (SEB, positive control). CD4 and CD8 T cell expression of IFN-γ and non-IFN-γ (IL-2, TNF) cytokines was measured by flow cytometry.RESULTSAmong 213 children, 28.6% had CFP-10/ESAT-6 CD4 and/or CD8 responses up to 24 months of age. No children with a positive Mtb-specific response had a reported known TB exposure. More children exhibited Mtb-specific non-IFN-γ+ (IL-2+ and/or TNF+) responses than IFN-γ+ responses (26.3% vs. 10.3%, p<0.001), including 18.3% identified by non-IFN-γ+ responses alone (non-IFN-γ+ alone 18.3% vs. IFN-γ+ alone 2.4%, p <0.001). Proportion of children with Mtb-specific responses were similar regardless of HIV exposure (cHEU 31.5% vs. cHUU 25.5%, p=0.33). At 6-10 weeks of age, children were more likely to have non-IFN-γ+ vs. IFN-γ+ responses to SEB (positive control) (96.3% vs. 77.8%, p=0.004); however, by 24 months of age 100% of children had both IFN-γ+ and non-IFN-γ+ SEB responses.CONCLUSIONMtb-specific CD4/CD8 responses were common among young Kenyan children up to 24 months of age, despite limited reported TB exposures. Non-IFN-γ+ T cell cytokine expression identified more children than IFN-γ+ who would be potentially missed by commercially available IGRAs.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"68 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146015190","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}
{"title":"CXCR6 in the Blood Is Not the Liver: Clarifying NK-Cell 'Homing' and Post-Cure ADCC Imprints in Acute Hepatitis C.","authors":"Anxin Wen","doi":"10.1093/infdis/jiag044","DOIUrl":"https://doi.org/10.1093/infdis/jiag044","url":null,"abstract":"","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"123 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146005028","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}
Silvia Lucena Lage,Joseph M Rocco,Cihan Oguz,Francisco Otaizo-Carrasquero,Adam Rupert,Kristin L Boswell,Brian P Epling,Logan Cook,Eduardo Pinheiro Amaral,Elizabeth Laidlaw,Frances Galindo,Richard A Koup,Princy Kumar,Rita Poon,Glenn W Wortmann,Andrea Lisco,Maura Manion,Irini Sereti
BACKGROUNDDespite the efficacy of therapeutics and vaccines in reducing risk of severe COVID-19, SARS-CoV-2 infections continue to occur and rebound symptoms after initial improvement has been well-described. The mechanisms driving COVID-19 rebound remain unclear.METHODSCritical inflammatory responses were assessed by Imagestream, flow cytometry and single-cell RNA sequencing in peripheral blood mononuclear cells from vaccinated individuals presenting with early [EA, 3 days post-infection (PI), n=6] or late (LA, 8 days PI, n=6) acute symptoms and clinical rebound (rebound, 16 days PI, n=8), as well as healthy volunteers (HV, n=7).RESULTSAn overall decline in key inflammatory responses is observed in groups with longer time from symptom onset when compared to EA infection. However, RNA sequencing revealed a partial resurgence of inflammatory, stress and antiviral responses during clinical rebound, with a unique cluster of monocytes with greater activation of antigen presentation pathways and type-I IFN signaling. Monocytes from patients with rebound COVID-19 also showed elevated inflammasome activation when compared to HV, along with an accumulation of oxidized lipids and decreased levels of glutathione, both hallmarks of the oxidative stress response. Inflammatory measurements positively associated with serum SARS-CoV-2 nucleocapsid antigen and inversely correlated with adaptive immune responses, suggesting adaptive immunity limits inflammation in patients with rebound.CONCLUSIONSOur findings potentially reflect viral reappearance post-treatment in participants with clinical rebound and outline mechanisms why rebound symptoms are typically milder than during acute presentations. Extending the antiviral treatment period and/or targeting inflammatory pathways could potentially prevent virological rebound or help mitigate associated symptoms.
{"title":"Inflammasome activation and oxidative stress in SARS-CoV-2 infection and symptomatic rebound.","authors":"Silvia Lucena Lage,Joseph M Rocco,Cihan Oguz,Francisco Otaizo-Carrasquero,Adam Rupert,Kristin L Boswell,Brian P Epling,Logan Cook,Eduardo Pinheiro Amaral,Elizabeth Laidlaw,Frances Galindo,Richard A Koup,Princy Kumar,Rita Poon,Glenn W Wortmann,Andrea Lisco,Maura Manion,Irini Sereti","doi":"10.1093/infdis/jiag037","DOIUrl":"https://doi.org/10.1093/infdis/jiag037","url":null,"abstract":"BACKGROUNDDespite the efficacy of therapeutics and vaccines in reducing risk of severe COVID-19, SARS-CoV-2 infections continue to occur and rebound symptoms after initial improvement has been well-described. The mechanisms driving COVID-19 rebound remain unclear.METHODSCritical inflammatory responses were assessed by Imagestream, flow cytometry and single-cell RNA sequencing in peripheral blood mononuclear cells from vaccinated individuals presenting with early [EA, 3 days post-infection (PI), n=6] or late (LA, 8 days PI, n=6) acute symptoms and clinical rebound (rebound, 16 days PI, n=8), as well as healthy volunteers (HV, n=7).RESULTSAn overall decline in key inflammatory responses is observed in groups with longer time from symptom onset when compared to EA infection. However, RNA sequencing revealed a partial resurgence of inflammatory, stress and antiviral responses during clinical rebound, with a unique cluster of monocytes with greater activation of antigen presentation pathways and type-I IFN signaling. Monocytes from patients with rebound COVID-19 also showed elevated inflammasome activation when compared to HV, along with an accumulation of oxidized lipids and decreased levels of glutathione, both hallmarks of the oxidative stress response. Inflammatory measurements positively associated with serum SARS-CoV-2 nucleocapsid antigen and inversely correlated with adaptive immune responses, suggesting adaptive immunity limits inflammation in patients with rebound.CONCLUSIONSOur findings potentially reflect viral reappearance post-treatment in participants with clinical rebound and outline mechanisms why rebound symptoms are typically milder than during acute presentations. Extending the antiviral treatment period and/or targeting inflammatory pathways could potentially prevent virological rebound or help mitigate associated symptoms.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"10 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146005032","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}
Anil K Chaturvedi,Gregory Haber,Barry I Graubard,Li C Cheung,Maura L Gillison,Rebecca Landy
HPV vaccination of US individuals aged 27-45 years is recommended through shared clinical decision-making. To enable shared decision-making, we used a microsimulation-based state-transition model to develop and validate a risk-prediction model to identify heterosexual men aged 27-45 at high-risk of acquiring oral HPV16 infections. A risk model for incident oral HPV16 infections had good discrimination (AUC=0.73) and calibration (E/O=1.01) in internal cross-validation. Compared to vaccinating all men aged 27-45, vaccinating 44% of men with highest model-predicted risk would prevent 80% of incident oral HPV16 infections through age 45 and reduce the NNV to prevent 1 infection by 45% (184 vs. 100).
{"title":"Risk-based prophylactic HPV vaccination of heterosexual US men aged 27 to 45 years for prevention of oropharyngeal cancer.","authors":"Anil K Chaturvedi,Gregory Haber,Barry I Graubard,Li C Cheung,Maura L Gillison,Rebecca Landy","doi":"10.1093/infdis/jiag038","DOIUrl":"https://doi.org/10.1093/infdis/jiag038","url":null,"abstract":"HPV vaccination of US individuals aged 27-45 years is recommended through shared clinical decision-making. To enable shared decision-making, we used a microsimulation-based state-transition model to develop and validate a risk-prediction model to identify heterosexual men aged 27-45 at high-risk of acquiring oral HPV16 infections. A risk model for incident oral HPV16 infections had good discrimination (AUC=0.73) and calibration (E/O=1.01) in internal cross-validation. Compared to vaccinating all men aged 27-45, vaccinating 44% of men with highest model-predicted risk would prevent 80% of incident oral HPV16 infections through age 45 and reduce the NNV to prevent 1 infection by 45% (184 vs. 100).","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"39 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146005035","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}
Jing Sun,Lolita S Nidadavolu,Hsing-Yu Hsu,Rohan G Rajagopal,Jacquie Astemborski,Yuqiong Wu,Yutong Jiang,Jonah B Sacha,Paul Kievit,Beth D Jamieson,Charles T Roberts,Gregory D Kirk,Todd T Brown,Peter M Abadir
BACKGROUNDCirculating cell-free mitochondrial DNA (ccf-mtDNA) fragments are released into the bloodstream following cell death and are associated with comorbidities seen in people with HIV-1 (PWH). However, ccf-mtDNA dynamics in acute and chronic HIV infection remain unclear.METHODSWe quantified short and long ccf-mtDNA fragments in serum from 2 cohorts of PWH and people without HIV (PWoH), collected at 1, 3, and 5 years in the first cohort (N = 890) and 1 and 5 years in the second (N = 427). Mixed-effect linear regression models were used to analyze longitudinal associations of ccf-mtDNA levels with HIV status and markers (CD4-cell count, viral load). In parallel, we examined ccf-mtDNA levels in nonhuman primates (NHPs) before and after simian immunodeficiency virus (SIV) infection and following 3 and 6 months of ART.RESULTSIn both human cohorts, PWH had significantly lower levels of short and long ccf-mtDNA fragments compared with PWoH. Individuals with lower CD4 T-cell counts exhibited further reductions in ccf-mtDNA levels. In NHPs, short ccf-mtDNA levels increased after infection, peaking before ART initiation (P = .001), and subsequently declined, reaching levels below baseline after 6 months on ART. Long ccf-mtDNA fragments remained stable during the early post-ART phase but declined significantly by 6 months (P = .02).CONCLUSIONSChronic HIV infection and treated SIV infection are associated with reduced ccf-mtDNA levels, particularly in advanced disease stages. Further research is needed to clarify their role in immune activation, chronic inflammation, and aging-related comorbidities in PWH and their applicability as clinically relevant biomarkers of these processes.
{"title":"Mitochondrial DNA Fragment Dynamics in Acute and Chronic Human Immunodeficiency Virus: Insights From Human and Nonhuman Primate Models.","authors":"Jing Sun,Lolita S Nidadavolu,Hsing-Yu Hsu,Rohan G Rajagopal,Jacquie Astemborski,Yuqiong Wu,Yutong Jiang,Jonah B Sacha,Paul Kievit,Beth D Jamieson,Charles T Roberts,Gregory D Kirk,Todd T Brown,Peter M Abadir","doi":"10.1093/infdis/jiag014","DOIUrl":"https://doi.org/10.1093/infdis/jiag014","url":null,"abstract":"BACKGROUNDCirculating cell-free mitochondrial DNA (ccf-mtDNA) fragments are released into the bloodstream following cell death and are associated with comorbidities seen in people with HIV-1 (PWH). However, ccf-mtDNA dynamics in acute and chronic HIV infection remain unclear.METHODSWe quantified short and long ccf-mtDNA fragments in serum from 2 cohorts of PWH and people without HIV (PWoH), collected at 1, 3, and 5 years in the first cohort (N = 890) and 1 and 5 years in the second (N = 427). Mixed-effect linear regression models were used to analyze longitudinal associations of ccf-mtDNA levels with HIV status and markers (CD4-cell count, viral load). In parallel, we examined ccf-mtDNA levels in nonhuman primates (NHPs) before and after simian immunodeficiency virus (SIV) infection and following 3 and 6 months of ART.RESULTSIn both human cohorts, PWH had significantly lower levels of short and long ccf-mtDNA fragments compared with PWoH. Individuals with lower CD4 T-cell counts exhibited further reductions in ccf-mtDNA levels. In NHPs, short ccf-mtDNA levels increased after infection, peaking before ART initiation (P = .001), and subsequently declined, reaching levels below baseline after 6 months on ART. Long ccf-mtDNA fragments remained stable during the early post-ART phase but declined significantly by 6 months (P = .02).CONCLUSIONSChronic HIV infection and treated SIV infection are associated with reduced ccf-mtDNA levels, particularly in advanced disease stages. Further research is needed to clarify their role in immune activation, chronic inflammation, and aging-related comorbidities in PWH and their applicability as clinically relevant biomarkers of these processes.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"65 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146005092","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}
{"title":"Beyond Transplantation: Cytomegalovirus Viremia as a Therapeutic Target in Non-Cytomegalovirus Syndromes.","authors":"Ghady Haidar","doi":"10.1093/infdis/jiaf648","DOIUrl":"https://doi.org/10.1093/infdis/jiaf648","url":null,"abstract":"","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"41 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145971882","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}
Background & Aims Limited research exists on immune checkpoint inhibitors (ICIs)’ antiviral efficacy in HBV-related hepatocellular carcinoma (HCC). This study aimed to evaluate the impact of ICIs on multiple HBV markers and its correlation with HCC prognosis. Methods A retrospective cohort study was performed on 318 HBV-related HCC patients, including 268 who received ICIs (with/without targeted therapy; ICI group) and 50 who received targeted therapy alone (non-ICI group). Levels of quantitative HBsAg (qHBsAg), HBV DNA, HBV RNA and HBcrAg were monitored. Tumor response was evaluated using RECIST 1.1. Results Over a median 8.1-month follow-up, the ICI group showed a significantly greater decrease in all HBV markers. At week 96, the ICI group showed significantly higher cumulative incidences of HBsAg response (loss or ≥0.5 Log10 decline) (41.6% vs. 14.9%, p=0.006) and HBcrAg response (negativity or ≥1 Log10 decline) (46.3% vs. 18.1%, p=0.007) than non-ICI group, and a significantly faster achievement rate of HBV RNA response (negativity or ≥0.5 Log10 decline) (HR: 1.80, 95% CI: 1.08-2.99, p=0.021). Notably, the PD-1 inhibitors showed significantly better virological response efficacy than PD-L1 inhibitors (HR=2.04-5.43). The patients with lower levels of HBV markers at enrollment demonstrated significantly better overall survival (OS). Moreover, patients achieving virological response were associated with significantly better survival outcomes and tumor response, with HR ranging 1.64-8.06. Conclusions ICIs demonstrate dual therapeutic effects in HBV-related HCC, significantly reducing multiple HBV markers while concurrently enhancing prognosis in combination with antiviral therapy, emphasizing the importance of sustained virological suppression for optimal HCC outcomes.
{"title":"Immune checkpoint inhibitor-induced rapid decline in HBV markers improves the prognosis of HBV-related hepatocellular carcinoma patients","authors":"Yujie Ran, Minghui Zhu, Kunyuan Wang, Ying Xia, Yun Zhu, Mengya Zang, Shuai Kang, Qi Li, Xiaoyun Hu, Ying Wang, Fang Liu, Xiaowei Chen, Qian Zhao, Hongyan Liu, Dingli Liu, Huaiyu Chen, Jinzhang Chen, Yabing Guo, Rong Fan","doi":"10.1093/infdis/jiag036","DOIUrl":"https://doi.org/10.1093/infdis/jiag036","url":null,"abstract":"Background & Aims Limited research exists on immune checkpoint inhibitors (ICIs)’ antiviral efficacy in HBV-related hepatocellular carcinoma (HCC). This study aimed to evaluate the impact of ICIs on multiple HBV markers and its correlation with HCC prognosis. Methods A retrospective cohort study was performed on 318 HBV-related HCC patients, including 268 who received ICIs (with/without targeted therapy; ICI group) and 50 who received targeted therapy alone (non-ICI group). Levels of quantitative HBsAg (qHBsAg), HBV DNA, HBV RNA and HBcrAg were monitored. Tumor response was evaluated using RECIST 1.1. Results Over a median 8.1-month follow-up, the ICI group showed a significantly greater decrease in all HBV markers. At week 96, the ICI group showed significantly higher cumulative incidences of HBsAg response (loss or ≥0.5 Log10 decline) (41.6% vs. 14.9%, p=0.006) and HBcrAg response (negativity or ≥1 Log10 decline) (46.3% vs. 18.1%, p=0.007) than non-ICI group, and a significantly faster achievement rate of HBV RNA response (negativity or ≥0.5 Log10 decline) (HR: 1.80, 95% CI: 1.08-2.99, p=0.021). Notably, the PD-1 inhibitors showed significantly better virological response efficacy than PD-L1 inhibitors (HR=2.04-5.43). The patients with lower levels of HBV markers at enrollment demonstrated significantly better overall survival (OS). Moreover, patients achieving virological response were associated with significantly better survival outcomes and tumor response, with HR ranging 1.64-8.06. Conclusions ICIs demonstrate dual therapeutic effects in HBV-related HCC, significantly reducing multiple HBV markers while concurrently enhancing prognosis in combination with antiviral therapy, emphasizing the importance of sustained virological suppression for optimal HCC outcomes.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"81 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145986380","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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