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Virology

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Insights into Absence of Lymphoma Despite Fulminant Epstein-Barr Virus Infection in Patients with XIAP Deficiency
Yizhe Sun, … , Steven P. Gygi, Benjamin E. Gewurz
Yizhe Sun, … , Steven P. Gygi, Benjamin E. Gewurz
Published July 17, 2025
Citation Information: JCI Insight. 2025. https://doi.org/10.1172/jci.insight.193787.
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Insights into Absence of Lymphoma Despite Fulminant Epstein-Barr Virus Infection in Patients with XIAP Deficiency

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Abstract

X-linked Lymphoproliferative Syndromes (XLP), arising from mutations in SH2D1A or XIAP genes, are characterized by fulminant Epstein-Barr Virus (EBV) infection. Lymphomas occur frequently in XLP-1 and in other congenital conditions with heightened EBV susceptibility, but not in XLP-2. Why XLP-2 patients are apparently protected from EBV-driven lymphomagenesis remains a key open question. To gain insights, newly EBV-infected versus receptor-stimulated primary B-cells from XLP-2 patients or with XIAP CRISPR editing were compared to healthy controls. XIAP perturbation impeded outgrowth of newly EBV-infected B-cells, but not that of CD40 ligand and interleukin-21 stimulated B-cells. XLP-2 deficient B-cells showed significantly lower EBV transformation efficiency than healthy controls. Interestingly, EBV-immortalized lymphoblastoid cell proliferation was not impaired by XIAP knockout, implicating an XIAP role in early EBV B-cell transformation. Mechanistically, nascent EBV infection activated p53-mediated apoptosis signaling, which was counteracted by XIAP in control cells. With XIAP deficiency, EBV markedly elevated apoptosis rates over the first two weeks of infection. Interferon-gamma, whose levels are increased with severe XLP2 EBV infection, markedly increased newly EBV-infected B-cell apoptosis. These findings underscored XIAP's crucial role in support of the earliest stages of EBV-mediated B-cell immortalization and provide insights into the curious absence of EBV+ lymphoma in XLP-2 patients.

Authors

Yizhe Sun, Janet Chou, Kevin D. Dong, Steven P. Gygi, Benjamin E. Gewurz

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Human pegivirus alters brain and blood immune and transcriptomic profiles of patients with Parkinson’s disease
Barbara A. Hanson, … , Rudolph J. Castellani, Igor J. Koralnik
Barbara A. Hanson, … , Rudolph J. Castellani, Igor J. Koralnik
Published July 8, 2025
Citation Information: JCI Insight. 2025;10(13):e189988. https://doi.org/10.1172/jci.insight.189988.
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Article has an altmetric score of 791

Human pegivirus alters brain and blood immune and transcriptomic profiles of patients with Parkinson’s disease

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Abstract

Parkinson’s disease (PD) is a neurodegenerative disorder with both genetic and environmental factors contributing to pathogenesis. Viral infections are potential environmental triggers that influence PD pathology. Using ViroFind, an unbiased platform for whole virome sequencing, along with quantitative PCR (qPCR), we identified human pegivirus (HPgV) in 5 of 10 (50%) of PD brains, confirmed by IHC in 2 of 2 cases, suggesting an association with PD. All 14 age- and sex-matched controls were HPgV negative. HPgV-brain positive patients with PD showed increased neuropathology by Braak stage and Complexin-2 levels, while those positive in the blood had higher IGF-1 and lower pS65-ubiquitin, supporting disruption in metabolism or mitophagy in response to HPgV. RNA-Seq revealed altered immune signaling in HPgV-infected PD samples, including consistent suppression of IL-4 signaling in both the brain and blood. Longitudinal analysis of blood samples showed a genotype-dependent viral response, with HPgV titers correlating directly with IL-4 signaling in a LRRK2 genotype–dependent manner. YWHAB was a key hub gene in the LRRK2 genotypic response, which exhibited an altered relationship with immune-related factors, including NFKB1, ITPR2, and LRRK2 itself, in patients with PD who are positive for HPgV. These results suggest a role for HPgV in shaping PD pathology and highlight the complex interplay between viral infection, immunity, and neuropathogenesis.

Authors

Barbara A. Hanson, Xin Dang, Pouya Jamshidi, Alicia Steffens, Kaleigh Copenhaver, Zachary S. Orban, Bernabe Bustos, Stephen J. Lubbe, Rudolph J. Castellani, Igor J. Koralnik

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Pan-H7 influenza human antibody virus neutralization depends on avidity and steric hindrance
Iuliia M. Gilchuk, … , Robert H. Carnahan, James E. Crowe Jr.
Iuliia M. Gilchuk, … , Robert H. Carnahan, James E. Crowe Jr.
Published June 5, 2025
Citation Information: JCI Insight. 2025. https://doi.org/10.1172/jci.insight.186182.
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Article has an altmetric score of 4

Pan-H7 influenza human antibody virus neutralization depends on avidity and steric hindrance

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Abstract

H7N9 avian influenza virus is a zoonotic influenza virus of public health concern, with a 39% mortality rate in humans. H7N9-specific prevention or treatments for humans have not been approved. We previously isolated a human monoclonal antibody (mAb) designated H7-235 that broadly reacts to diverse H7 viruses and neutralizes H7N9 viruses in vitro. Here, we report the crystal structure of H7 HA1 bound to the fragment antigen-binding region (Fab) of recombinant H7-235 (rH7-235). The crystal structure revealed that rH7-235 recognizes residues near but outside of the receptor binding site (RBS). Nevertheless, the rH7-235 IgG potently inhibits hemagglutination mediated by H7N9 viruses due to avidity effect and Fc steric hindrance. This mAb prophylactically protects mice against weight loss and death caused by challenge with lethal H7N9 viruses in vivo. rH7-235 mAb neutralizing activity alone is sufficient for protection when used at high dosed in a prophylactic setting. This study provides insights into mechanisms of viral neutralization by protective broadly reactive anti-H7 antibodies informing the rational design of therapeutics and vaccines against H7N9 influenza virus.

Authors

Iuliia M. Gilchuk, Jinhui Dong, Ryan P. Irving, Cameron D. Buchman, Erica Armstrong, Hannah L. Turner, Sheng Li, Andrew B. Ward, Robert H. Carnahan, James E. Crowe Jr.

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Early multiple sclerosis activity associated with TBX21+CD21loCXCR3+ B cell expansion resembling EBV-induced phenotypes
Elliott D. SoRelle, … , Simon G. Gregory, Micah A. Luftig
Elliott D. SoRelle, … , Simon G. Gregory, Micah A. Luftig
Published May 13, 2025
Citation Information: JCI Insight. 2025. https://doi.org/10.1172/jci.insight.188543.
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Article has an altmetric score of 21

Early multiple sclerosis activity associated with TBX21+CD21loCXCR3+ B cell expansion resembling EBV-induced phenotypes

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Abstract

Epstein-Barr virus (EBV) infection precedes multiple sclerosis (MS) onset and plays a poorly understood etiologic role. To investigate possible viral pathogenesis, we analyzed single-cell expression in peripheral B cells from people with early MS collected longitudinally during the Immune Tolerance Network (ITN) STAyCIS Trial. Expression profiles were compared to scRNA-seq from in vitro EBV models, autoimmune disorders, chronic infectious diseases, and healthy controls. Analyses focused on CD19+/CD20+/CD21lo/CD11c+/T-bet+ atypical B cells (ABCs). ABCs were significantly enriched in early MS PBMCs versus healthy controls by scRNA-seq and flow cytometry, establishing ABC expansion as a clinical feature. EBV-associated ABC expression including CXCR3, PD-L1, and PD-L2 was enriched in early MS; however, direct EBV infection of ABCs was not detected. Early MS ABCs exhibited significantly upregulated inflammatory cytokine mRNAs (CXCL8, IL18, VEGFA). Further de novo EBV-infected B cells secreted IL-8 and VEGF. MS activity stratification revealed rare distinctive inflammatory ABCs significantly underrepresented in individuals with no evidence of activity long-term (LTNA) versus people with additional RRMS activity at the primary endpoint. Moreover, CXCR3+ ABCs increased after baseline diagnosis and were significantly enriched in people with disease exacerbation during the study. Thus, ABC expansion and inflammatory responses correlate to early MS activity, possibly as a bystander response to EBV.

Authors

Elliott D. SoRelle, Ellora Haukenfrers, Gillian Q. Horn, Vaibhav Jain, James Giarraputo, Karen Abramson, Emily Hocke, Laura A. Cooney, Kristina M. Harris, Scott S. Zamvil, Simon G. Gregory, Micah A. Luftig

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Remdesivir post-exposure prophylaxis limits measles-induced “immune amnesia” and measles antibody responses in macaques
Andy Kwan Pui Chan, … , H. Benjamin Larman, Diane E. Griffin
Andy Kwan Pui Chan, … , H. Benjamin Larman, Diane E. Griffin
Published April 30, 2025
Citation Information: JCI Insight. 2025. https://doi.org/10.1172/jci.insight.190740.
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Article has an altmetric score of 7

Remdesivir post-exposure prophylaxis limits measles-induced “immune amnesia” and measles antibody responses in macaques

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Abstract

Measles remains one of the most important causes of worldwide morbidity and mortality in children. Measles virus (MeV) replicates extensively in lymphoid tissue and most deaths are due to other infectious diseases associated with MeV-induced loss of circulating antibodies to other pathogens. To determine whether remdesivir, a broad-spectrum direct-acting antiviral, affects MeV-induced loss of antibody to other pathogens, we expanded the VirScan technology to detect antibody to both human and macaque pathogens. We measured the antibody reactivity to MeV and non-MeV viral peptides using plasma from MeV-infected macaques that received remdesivir either as post-exposure prophylaxis (d3-14, PEP) or as late treatment (d11-22, LT) in comparison with macaques that were not treated. Remdesivir PEP, but not LT, limited the loss of antibody to non-MeV pathogens. Remdesivir PEP also limited the antibody response to MeV with a decrease in both the magnitude and breadth of the epitopes recognized. LT had little effect on the magnitude of the MeV-specific antibody response but affected the breadth of the response. Therefore, early, but not late, treatment of measles with the direct-acting antiviral remdesivir prevents the loss of antibody to other pathogens but decreases the response to MeV.

Authors

Andy Kwan Pui Chan, Liting Liu, William R. Morgenlander, Manjusha Thakar, Nadine A. Peart Akindele, Jacqueline Brockhurst, Shristi Ghimire, Maggie L. Bartlett, Kelly A. Metcalf Pate, Victor C. Chu, Meghan S. Vermillion, Danielle P. Porter, Tomas Cihlar, Michael J. Mina, H. Benjamin Larman, Diane E. Griffin

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SARS-CoV-2 ORF8 drives osteoclastogenesis in preexisting immune-mediated inflammatory diseases
Ivonne Melano, … , Suan-Sin Foo, Weiqiang Chen
Ivonne Melano, … , Suan-Sin Foo, Weiqiang Chen
Published December 20, 2024
Citation Information: JCI Insight. 2024;9(24):e178820. https://doi.org/10.1172/jci.insight.178820.
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Article has an altmetric score of 50

SARS-CoV-2 ORF8 drives osteoclastogenesis in preexisting immune-mediated inflammatory diseases

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Abstract

Patients with immune-mediated inflammatory diseases (IMIDs) like rheumatoid arthritis (RA) are at higher risk for severe COVID-19 and long-term complications in bone health. Emerging clinical evidence demonstrated that SARS-CoV-2 infection reduces bone turnover and promotes bone loss, but the mechanism underlying worsened bone health remains elusive. This study sought to identify specific immune mediators that exacerbated preexisting IMIDs after SARS-CoV-2 exposure. Plasma samples from 4 groups were analyzed: healthy, IMID only, COVID-19 only, and COVID-19 + IMID. Using high-throughput multiplexed proteomics, we profiled 1,500 protein biomarkers and identified 148 unique biomarkers in COVID-19 patients with IMIDs, including elevated inflammatory cytokines (e.g., IL-17F) and bone resorption markers. Long-term circulating SARS-CoV-2 ORF8, a virulence factor for COVID-19, was detected in the COVID + IMID group. RA was one of the most common IMIDs in our study. ORF8 treatment of RA-derived human osteoblasts (RA-hOBs) increased levels of inflammatory (TNF, IL6, CCL2) and bone resorption (RANKL/osteoprotegerin ratio) markers compared with healthy controls. Supernatants from ORF8-treated RA-hOBs drove the differentiation of macrophages into osteoclast-like cells. These findings suggest that SARS-CoV-2 exposure can exacerbate IMIDs through ORF8-driven inflammation and osteoclastogenesis, highlighting potential therapeutic targets for managing COVID-19–induced bone pathologies.

Authors

Ivonne Melano, Tamiris Azamor, Camila C.S. Caetano, Nikki M. Meyer, Chineme Onwubueke, Anabelle Visperas, Débora Familiar-Macedo, Gielenny M. Salem, Brandy-Lee Soos, Cassandra M. Calabrese, Youn Jung Choi, Shuyang Chen, Younho Choi, Xianfang Wu, Zilton Vasconcelos, Suzy A.A. Comhair, Karin Nielsen-Saines, Leonard H. Calabrese, M. Elaine Husni, Jae U. Jung, Nicolas S. Piuzzi, Suan-Sin Foo, Weiqiang Chen

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Rapid systemic spread and minimal immune responses following SIVsab intrarectal transmission in African green monkeys
Kevin D. Raehtz, … , Cristian Apetrei, Ivona Pandrea
Kevin D. Raehtz, … , Cristian Apetrei, Ivona Pandrea
Published December 6, 2024
Citation Information: JCI Insight. 2024;9(23):e183751. https://doi.org/10.1172/jci.insight.183751.
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Article has an altmetric score of 5

Rapid systemic spread and minimal immune responses following SIVsab intrarectal transmission in African green monkeys

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Abstract

African green monkeys (AGMs) are natural hosts of SIV whose infection does not progress to AIDS. Since early events of infection may be critical to pathogenesis in nonnatural hosts, we investigated early SIV infection in 29 adult male AGMs intrarectally inoculated with SIVsab92018 (SIVsab) and serially sacrificed throughout acute into early chronic infection to understand patterns of viral establishment, dissemination, and their effect on disease progression. Using this model, we showed that foci of virus replication could be detected at the site of inoculation and in the draining lymphatics as early as 1–3 days postinfection (dpi). Furthermore, testing with ultrasensitive assays showed rapid onset of viremia (2–4 dpi). After systemic spread, virus was detected in all tissues surveyed. Multiple transmitted/founder viruses were identified, confirming an optimal challenge dose, while demonstrating a moderate mucosal genetic bottleneck. Resident CD4+ T cells were the initial target cells; other immune cell populations were not significantly altered at the site of entry. Thus, intrarectal SIVsab infection is characterized by swift dissemination of the virus, a lack of major target cell recruitment, and no window of opportunity for interventions to prevent virus dissemination during the earliest stages of infection, similar to intrarectal transmission but different from vaginal transmission in macaques.

Authors

Kevin D. Raehtz, Cuiling Xu, Claire Deleage, Dongzhu Ma, Benjamin B. Policicchio, Egidio Brocca-Cofano, Daniele Piccolo, Kathryn Weaver, Brandon F. Keele, Jacob D. Estes, Cristian Apetrei, Ivona Pandrea

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Variation in HIV-1 Tat activity is a key determinant in the establishment of latent infection
Francisco Gomez-Rivera, … , Marianne E. Yaple-Maresh, Kathleen L. Collins
Francisco Gomez-Rivera, … , Marianne E. Yaple-Maresh, Kathleen L. Collins
Published December 5, 2024
Citation Information: JCI Insight. 2024. https://doi.org/10.1172/jci.insight.184711.
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Article has an altmetric score of 6

Variation in HIV-1 Tat activity is a key determinant in the establishment of latent infection

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Abstract

Despite effective treatment, Human immunodeficiency virus (HIV) persists in optimally treated people as a transcriptionally silent provirus. Latently infected cells evade the immune system and the harmful effects of the virus, thereby creating a long-lasting reservoir of HIV. To gain a deeper insight into the molecular mechanisms of HIV latency establishment, we constructed a series of HIV-1 fluorescent reporter viruses that distinguish active versus latent infection. We unexpectedly observed that the proportion of active-to-latent infection depended on a limiting viral factor, which created a bottle neck that could be overcome by superinfection of the cell, T cell activation or overexpression of HIV-1 trans activator of transcription (Tat). In addition, we found that tat and rev expression levels vary amongst HIV molecular clones and that tat levels were an important variable in latency establishment. Lower rev levels limited viral protein expression whereas lower Tat levels or mutation of the Tat binding element promoted latent infection that was resistant to reactivation even in fully activated primary T cells. Nevertheless, we found that combinations of latency reversal agents targeting both cellular activation and histone acetylation pathways overcame deficiencies in the Tat-TAR axis of transcription regulation. These results provide additional insight into the mechanisms of latency establishment and inform Tat-centered approaches to cure HIV.

Authors

Francisco Gomez-Rivera, Valeri H. Terry, Cuie Chen, Mark M. Painter, Maria C. Virgilio, Marianne E. Yaple-Maresh, Kathleen L. Collins

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Repurposing of lonafarnib as a treatment for SARS-CoV-2 infection
Mohsin Khan, … , Irving C. Allen, T. Jake Liang
Mohsin Khan, … , Irving C. Allen, T. Jake Liang
Published December 3, 2024
Citation Information: JCI Insight. 2024. https://doi.org/10.1172/jci.insight.182704.
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Article has an altmetric score of 4

Repurposing of lonafarnib as a treatment for SARS-CoV-2 infection

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Abstract

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes Coronavirus disease 2019 (COVID-19), has emerged as a global pandemic pathogen with high mortality. While treatments have been developed to reduce morbidity and mortality of COVID-19, more antivirals with broad-spectrum activities are still needed. Here we identified lonafarnib (LNF), a Food and Drug Administration (FDA)-approved drug inhibitor of cellular farnesyltransferase (FTase), as an effective anti-SARS-CoV-2 agent. LNF inhibited SARS-CoV-2 infection and acted synergistically with known anti-SARS antivirals. LNF was equally active against diverse SARS-CoV-2 variants. Mechanistic studies suggested that LNF targeted multiple steps of viral life cycle. Using other structurally diverse FTase inhibitors and LNF-resistant FTase mutant, we demonstrated a key role of FTase in SARS-CoV-2 life cycle. To demonstrate in vivo efficacy, we infected SARS-CoV-2 susceptible humanized mice expressing human angiotensin-converting enzyme 2 (ACE2) and treated them with LNF. LNF at clinically relevant dose suppressed viral titer in the respiratory tract and improved pulmonary pathology and clinical parameters. Our study demonstrated that LNF, an approved oral drug with excellent human safety data, is a promising antiviral against SARS-CoV-2 that warrants further clinical assessment for treatment of COVID-19 and potentially other viral infections.

Authors

Mohsin Khan, Parker Irvin, Seung Bum Park, Hannah M. Ivester, Inna Ricardo-Lax, Madeleine Leek, Ailis Grieshaber, Eun Sun Jang, Sheryl L. Coutermarsh-Ott, Qi Zhang, Nunziata Maio, Jian-Kang Jiang, Bing Li, Wenwei Huang, Amy Q. Wang, Xin Xu, Zongyi Hu, Wei Zheng, Yihong Ye, Tracey Rouault, Charles M. Rice, Irving C. Allen, T. Jake Liang

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Profound reduction of HIV-1 reservoir cells over three decades of antiretroviral therapy started in early infancy
Liliana C. Vela, … , Katherine Luzuriaga, Mathias Lichterfeld
Liliana C. Vela, … , Katherine Luzuriaga, Mathias Lichterfeld
Published November 14, 2024
Citation Information: JCI Insight. 2024. https://doi.org/10.1172/jci.insight.186550.
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Article has an altmetric score of 6

Profound reduction of HIV-1 reservoir cells over three decades of antiretroviral therapy started in early infancy

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Abstract

HIV-1 reservoir cells persist indefinitely during suppressive antiretroviral therapy (ART) in individuals who acquire infection in adulthood, but little is known about the longitudinal evolution of viral reservoir cells during long-term ART started during early infancy. We studied two fraternal twins who acquired HIV-1 perinatally, started ART at week 10 after birth and remained on ART for 28 years. We observed that the frequency of genome intact proviruses, determined by single-genome near full-length proviral sequencing, declined by approximately 4,000- to 13,000-fold during this period, indicating enhanced decay rates of intact proviruses even after adjusting for dilution effects from somatic growth. Despite analyzing more than one billion PBMC after 28 years of ART in each participant, no intact proviruses were detected in one participant, and one intact provirus was isolated in the other. The longitudinal decline of defective proviruses in the two participants was more similar to proviral decay kinetics reported in individuals who started ART during adulthood; moreover, clonal sequence clusters were readily detectable for defective proviruses but not for intact proviruses after 28 years of ART in the two twins. Together, these data suggest decreased long-term stability and increased immunological vulnerability of intact proviruses during long-term ART started in early infancy.

Authors

Liliana C. Vela, Leah Carrere, Chloe Naasz, Sruthi Kalavacherla, Toong Seng Tan, Lesley de Armas, Ce Gao, Xu G. Yu, Savita G. Pahwa, Katherine Luzuriaga, Mathias Lichterfeld

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