Clinical Research and Public Health
Citation Information: J Clin Invest. 2025. https://doi.org/10.1172/JCI194081.
Abstract
Antiretroviral therapy (ART) prevents HIV-1 replication but does not eliminate the latent reservoir, the source of viral rebound if treatment is stopped. Autologous neutralizing antibodies (aNAbs) can block in vitro outgrowth of a subset of reservoir viruses and therefore potentially affect viral rebound upon ART interruption. We investigated aNAbs in 31 people with HIV-1 (PWH) on ART. Participants fell into two groups based on a high or low fraction of aNAb-resistant reservoir isolates, with most isolates being aNAb-resistant (IC50 >100 μg/ml). Time on uninterrupted ART was associated with higher aNAb resistance. However, pharmacodynamic analysis predicted that many isolates would be partially inhibited at physiologic IgG concentrations, to the same degree as by single antiretroviral drugs. Steep dose-response curve slopes, an indication of cooperativity, were observed for the rare isolates that were very strongly inhibited (>5 logs) by aNAbs. Resistance to aNAbs was not fully explained by declining in aNAb titers and may be driven partially by ADCC-mediated elimination of infected cells carrying aNAb-sensitive viruses over long time intervals, leaving only aNAb-resistant viruses which can contribute to viral rebound.
Authors
Natalie F. McMyn, Joseph Varriale, Hanna W. S. Wu, Vivek Hariharan, Milica Moskovljevic, Toong Seng Tan, Jun Lai, Anushka Singhal, Kenneth Lynn, Karam Mounzer, Pablo Tebas, Luis J. Montaner, Rebecca Hoh, Xu G. Yu, Mathias Lichterfeld, Francesco R. Simonetti, Colin Kovacs, Steven G. Deeks, Janet M. Siliciano, Robert F. Siliciano
Citation Information: J Clin Invest. 2025. https://doi.org/10.1172/JCI192589.
Abstract
Background: Anti-TNF biologics are widely used to treat patients with immune-mediated inflammatory diseases. In mouse models, the complete absence of TNF impairs germinal center (GC) responses. Less is known about the impact of anti-TNF therapy on specific immune responses in humans. Widespread vaccination against SARS-CoV-2 offered an unprecedented opportunity to investigate the effects of biological therapies on responses to specific immunization. Previous work demonstrated that inflammatory bowel disease (IBD) patients treated with anti-TNF biologics exhibit decreased Spike-specific antibody responses compared to IBD patients treated with anti-IL-12/23 or healthy controls, even after four doses of mRNA vaccine. Methods: Here we analyzed humoral responses to SARS-CoV-2 immunization using single-cell RNA-Sequencing and flow cytometry of Spike-specific memory B cells (MBC), as well as avidity measurements of plasma antibodies from IBD patients treated with anti-TNF or anti-IL-12/23 or from healthy controls. Results: We observed decreased somatic hypermutation in the B cell receptors of Spike-specific MBCs and decreased antigen-specific MBC accumulation following SARS-CoV-2 mRNA vaccination in anti-TNF treated IBD patients, compared to IBD patients treated with anti-IL-12/23 or healthy controls. This decreased somatic hypermutation in Spike-specific MBCs in anti-TNF treated patients correlated with decreased and delayed antibody affinity maturation and reduced neutralization activity. Conclusion: These data provide in vivo evidence that anti-TNF, but not anti-IL-12/23, therapy impairs the quantity and quality of antigen-specific GC outputs in humans. Funding: Juan and Stefania Speck (donation) and by Canadian Institutes of Health Research (CIHR)/COVID-Immunity Task Force (CITF) grants VR-1 172711, VS1-175545, GA2-177716, GA1-177703 and CIHR FDN 143301 &143350.
Authors
Michelle W. Cheung, Samantha Xu, Janna R. Shapiro, Freda Qi, Melanie Delgado-Brand, Karen Colwill, Roya Dayam, Ying Liu, Jenny Choi, Joanne M. Stempak, James M. Rini, Vinod Chandran, Mark S. Silverberg, Anne-Claude Gingras, Tania H. Watts
Citation Information: J Clin Invest. 2025. https://doi.org/10.1172/JCI177813.
Abstract
BACKGROUND. Endocrine therapy (ET) with tamoxifen (TAM) or aromatase inhibitors (AI) is highly effective against hormone receptor (HR) positive early breast cancer (BC), but resistance remains a major challenge. The primary objectives of our study were to understand the underlying mechanisms of primary resistance and to identify potential biomarkers. METHODS. We selected >800 patients in three sub-cohorts (Discovery, N=364, matched pairs), Validation 1, N=270, Validation 2, N= 176) of the West German Study Group (WSG) Adjuvant Dynamic marker-Adjusted Personalized Therapy (ADAPT) trial who underwent short-term pre-operative TAM or AI treatment. Treatment response was assessed by immunohistochemical labeling of proliferating cells with Ki67 before and after ET. We performed comprehensive molecular profiling, including targeted next-generation sequencing (NGS) and DNA methylation analysis using EPIC arrays, on post-treatment tumor samples. RESULTS.TP53 mutations were strongly associated with primary resistance to both TAM and AI. In addition, we identified distinct DNA methylation patterns in resistant tumors, suggesting alterations in key signaling pathways and tumor microenvironment composition. Based on these findings and patient age, we developed the Predictive Endocrine ResistanCe Index (PERCI). PERCI accurately stratified responders and non-responders in both treatment groups in all three sub-cohorts and predicted progression-free survival in an external validation cohort and in the combined sub-cohorts. CONCLUSION. Our results highlight the potential of PERCI to guide personalized endocrine therapy and improve patient outcomes. TRIAL REGISTRATION. WSG-ADAPT, ClinicalTrials.gov NCT01779206, Registered 2013-01-25, retrospectively registered.
Authors
Guokun Zhang, Vindi Jurinovic, Stephan Bartels, Matthias Christgen, Henriette Christgen, Leonie Donata Kandt, Lidiya Mishieva, Hua Ni, Mieke Raap, Janin Klein, Anna-Lena Katzke, Winfried Hofmann, Doris Steinemann, Ronald E. Kates, Oleg Gluz, Monika Graeser, Sherko Kuemmel, Ulrike Nitz, Christoph Plass, Ulrich Lehmann, Christine zu Eulenburg, Ulrich Mansmann, Clarissa Gerhauser, Nadia Harbeck, Hans H. Kreipe
Citation Information: J Clin Invest. 2025. https://doi.org/10.1172/JCI189300.
Abstract
BACKGROUND. Predicting individual vaccine responses is a substantial public health challenge. We developed immunaut, an open-source, data-driven framework for systems vaccinologists to analyze and predict immunological outcomes across diverse vaccination settings, beyond traditional assessments. METHODS. Using a comprehensive live attenuated influenza vaccine (LAIV) dataset from 244 Gambian children, immunaut integrated pre- and post-vaccination humoral, mucosal, cellular, and transcriptomic data. Through advanced modeling, our framework provided a holistic, systems-level view of LAIV-induced immunity. RESULTS. The analysis identified three distinct immunophenotypic profiles driven by baseline immunity: (1) CD8 T-cell responders with strong pre-existing immunity boosting memory T-cell responses; (2) Mucosal responders with prior influenza A virus immunity developing robust mucosal IgA and subsequent influenza B virus seroconversion; and (3) Systemic, broad influenza A virus responders starting from immune naivety who mounted broad systemic antibody responses. Pathway analysis revealed how pre-existing immune landscapes and baseline features, such as mucosal preparedness and cellular support, quantitatively dictate vaccine outcomes. CONCLUSION. Our findings emphasize the power of integrative, predictive frameworks for advancing precision vaccinology. The immunaut framework is a valuable resource for deciphering vaccine response heterogeneity and can be applied to optimize immunization strategies across diverse populations and vaccine platforms. FUNDING. Wellcome Trust (110058/Z/15/Z); Bill & Melinda Gates Foundation (INV-004222); HIC-Vac consortium; NIAID (R21 AI151917); NIAID CEIRR Network (75N93021C00045).
Authors
Stephanie Hao, Ivan Tomic, Benjamin B. Lindsey, Ya Jankey Jagne, Katja Hoschler, Adam Meijer, Juan Manuel Carreño Quiroz, Philip Meade, Kaori Sano, Chikondi Peno, André G. Costa-Martins, Debby Bogaert, Beate Kampmann, Helder Nakaya, Florian Krammer, Thushan I. de Silva, Adriana Tomic
Citation Information: J Clin Invest. 2025. https://doi.org/10.1172/JCI192920.
Abstract
Patients with sickle cell disease (SCD) frequently receive red blood cell (RBC) units stored near the end of their permissible storage life. To evaluate whether storage duration influences recipient metabolism, clinical chemistry and hematological parameters, we conducted a prospective, randomized, blinded trial comparing transfusions of RBC units stored for ≤10 days versus ≥30 days. Chronically transfused adults with SCD (N=24) received three consecutive outpatient transfusions with randomized-age RBCs, and blood samples from units and recipients were analyzed by metabolomics and clinical chemistry. Transfusion of short-stored units resulted in significantly higher circulating levels of 2,3-bisphosphoglycerate, an essential regulator of oxygen unloading, up to two weeks post-transfusion. Conversely, transfusions of long-stored RBCs were associated with lower hemoglobin and RBC increments, higher iron and transferrin saturation, pro-inflammatory cytokines and metabolites, oxidative stress and markers of renal dysfunction. Plasma and RBC metabolomic profiles revealed time- and storage-age-dependent alterations, particularly affecting glycolysis, purine, and sphingolipid metabolism. Transfusion of long-stored RBCs consistently worsened laboratory surrogates of oxygen delivery and RBC efficacy, and increased the circulating levels of immunomodulatory metabolites and pro-inflammatory cytokines. These findings highlight metabolic and hematologic advantages associated with transfusing fresher RBCs in adults with SCD, independent of immediate clinical outcomes.
Authors
Matthew S. Karafin, Abby L. Grier, Ross M. Fasano, Anton Ilich, David Wichlan, Ada Chang, Sonjile M. James, Hailly E. Butler, Oleg Kolupaev, Melissa C. Caughey, Daniel J Stephenson, Julie A. Reisz, Nigel S. Key, Joshua J. Field, Jane A. Little, Steven L. Spitalnik, Angelo D’Alessandro
Citation Information: J Clin Invest. 2025. https://doi.org/10.1172/JCI190736.
Abstract
BACKGROUND. Reversal reactions (RR) in leprosy are acute immune episodes marked by inflammation and bacterial clearance, offering a model to study the dynamics of host responses to Mycobacterium leprae. These episodes are often severe and difficult to treat, frequently progressing to permanent disabilities. We aimed to characterize the immune mechanisms and identify antimicrobial effectors during RR. METHODS. We performed RNA sequencing on paired skin biopsy specimens from nine leprosy patients collected before and at RR diagnosis, followed by differential gene expression and functional analysis. A machine learning classifier was applied to predict membrane-permeabilizing proteins. Antimicrobial activity was assessed in M. leprae-infected macrophages and axenic cultures. RESULTS. In the paired pre-RR and RR biopsy specimens, a 64-gene antimicrobial response signature was upregulated during RR and correlated with reduced M. leprae burden. Predicted upstream regulators included IL-1β, TNF, IFN-γ, and IL-17, indicating activation of both Th1 and Th17 pathways. A machine learning classifier identified 28 genes with predicted membrane-permeabilizing antimicrobial activity, including S100A8. Four proteins (S100A7, S100A8, CCL17, CCL19) demonstrated antimicrobial activity against M. leprae in vitro. Scanning electron microscopy revealed membrane damage in bacteria exposed to these proteins. CONCLUSION. RR is associated with a robust antimicrobial gene program regulated by Th1/Th17 cytokines. We identified potentially novel host antimicrobial effectors that exhibit activity against M. leprae, suggesting potential strategies to bolster Th1/Th17 responses for combating intracellular mycobacterial infections. FUNDING. NIH grants R01 AI022553, R01 AR040312, R01 AR073252, R01 AI166313, R01 AI169526, P50 AR080594, 4R37 AI052453-21, and NSF grant DMR2325840.
Authors
Priscila R. Andrade, Feiyang Ma, Jing Lu, Jaime de Anda, Ernest Y. Lee, George W. Agak, Craig J. Dobry, Bruno J. de Andrade Silva, Rosane M.B. Teles, Lilah A. Mansky, Jonathan Perrie, Dennis J. Montoya, Bryan D. Bryson, Johann E. Gudjonsson, Gerard C.L. Wong, Euzenir N. Sarno, Matteo Pellegrini, Robert L. Modlin
Citation Information: J Clin Invest. 2025. https://doi.org/10.1172/JCI181893.
Abstract
BACKGROUND. Axicabtagene ciloleucel (axi-cel), anti-CD19 chimeric antigen receptor (CAR) T-cell therapy demonstrated remarkable efficacy with manageable toxicity in relapsed/refractory indolent B-cell lymphomas in the ZUMA-5 trial. METHODS. Here, we report associations of product attributes, serum biomarkers, clinical features, and tumor characteristics with outcome in 124 follicular lymphoma (FL) patients. RESULTS. In univariate and multivariate analyses, pre-treatment inflammatory markers, including TNFα and IL12p40, as well as total metabolic tumor volume (TMTV) associated with disease progression. Conversely, T-naïve-like product phenotype associated with improved outcome, particularly in high TMTV patients. These covariates improved risk stratification when combined with the FL International Prognostic Index. Post-infusion, CAR T-cell expansion associated with improved outcome, while serum inflammatory and immuno-modulatory markers, including TNFα associated with disease progression and occurrence of high-grade cytokine release syndrome or neurologic events, presenting targets to improve the therapeutic index of axi-cel in FL. Tumor gene expression profiling revealed that both type I and II IFN signaling associated with disease progression and higher expression of T cell exhaustion markers, including TIM3 and LAG3. Pre- or post-treatment CD19 expression on tumor was not associated with outcome. CONCLUSION. These findings offer insights into mechanisms of resistance and toxicity, risk stratification, and strategies for development of next generation CAR-T approaches. TRIAL REGISTRATION. ClinicalTrials.gov NCT03105336. FUNDING. Kite, a Gilead Company.
Authors
Soumya Poddar, Jiali Yan, Gayatri Tiwari, Darawan Rinchai, Justin Budka, Wangshu Zhang, Weixin Peng, Shruti Salunkhe, Madison Davis, Qinghua Song, Sara Beygi, Harry Miao, Mike Mattie, Rhine S. Shen, Caron A. Jacobson, Davide Bedognetti, Simone Filosto, Sattva S. Neelapu
Citation Information: J Clin Invest. 2025. https://doi.org/10.1172/JCI191107.
Abstract
BACKGROUND. Telomere biology disorders (TBDs) exhibit incomplete penetrance and variable expressivity, even among individuals harboring the same pathogenic variant. We assessed whether common genetic variants associated with telomere length combine with large-effect variants to impact penetrance and expressivity in TBDs. METHODS. We constructed polygenic scores (PGS) for telomere length in the UK Biobank to quantify common variant burden, and assessed the PGS distribution across patient cohorts and biobanks to determine whether individuals with severe TBD presentations have increased polygenic burden causing short telomeres. We also characterized rare TBD variant carriers in the UK Biobank. RESULTS. Individuals with TBDs in cohorts enriched for severe pediatric presentations have polygenic scores predictive of short telomeres. In the UK Biobank, we identify carriers of pathogenic TBD variants who are enriched for adult-onset manifestations of TBDs. Unlike individuals in disease cohorts, the PGS of adult carriers do not show a common variant burden for shorter telomeres, consistent with the absence of childhood-onset disease. Notably, TBD variant carriers are enriched for idiopathic pulmonary fibrosis diagnoses, and telomere length PGS stratifies pulmonary fibrosis risk. Finally, common variants affecting telomere length were enriched in enhancers regulating known TBD genes. CONCLUSION. Common genetic variants combine with large-effect causal variants to impact clinical manifestations in rare TBDs. These findings offer a framework for understanding phenotypic variability in other presumed monogenic disorders. FUNDING. This work was supported by National Institutes of Health grants R01DK103794, R01HL146500, R01CA265726, R01CA292941, and the Howard Hughes Medical Institute.
Authors
Michael Poeschla, Uma P. Arora, Amanda Walne, Lisa J. McReynolds, Marena R. Niewisch, Neelam Giri, Logan P. Zeigler, Alexander Gusev, Mitchell J. Machiela, Hemanth Tummala, Sharon A. Savage, Vijay G. Sankaran
Citation Information: J Clin Invest. 2025. https://doi.org/10.1172/JCI189511.
Abstract
BACKGROUND. Treatment of tubo-ovarian high-grade serous carcinoma (HGSC) includes cytoreductive surgery, platinum-based chemotherapy, and often poly (ADP-ribose) polymerase (PARP) inhibitors. While homologous recombination (HR)-deficiency is a well-established predictor of therapy sensitivity, over 50% of HR-proficient HGSC also exhibit sensitivity. Currently, there are no biomarkers to identify which HR-proficient HGSCs will be sensitive to standard-of-care therapy. Replication stress may serve as a key determinant of response. METHODS. We evaluated phospho-RPA2-T21 (pRPA2) foci via immunofluorescence as a biomarker of replication stress in formalin-fixed, paraffin-embedded HGSC samples collected at diagnosis from patients treated with platinum chemotherapy (discovery cohort: n=31, validation cohort: n=244) or PARP inhibitors (n=63). Recurrent HGSCs (n=38) were also analyzed. pRPA2 score was calculated using automated imaging analysis. RESULTS. Samples were defined as pRPA2-High if >16% of cells had ≥2 pRPA2 foci on automated analysis. In the discovery cohort, HR-proficient, pRPA2-High HGSCs demonstrated significantly higher rates of a chemotherapy response score of 3 to platinum chemotherapy than HR-proficient, pRPA2-Low HGSCs. In the validation cohort, patients with HR-proficient, pRPA2-High HGSCs had significantly longer survival after platinum treatment than those with HR-proficient, pRPA2-Low HGSCs. Additionally, the pRPA2 assay effectively predicted survival outcomes in patients treated with PARP inhibitors and in recurrent HGSC samples. CONCLUSION. Our study underscores the importance of considering replication stress marker, such as pRPA2, alongside HR status in therapeutic planning. This approach has the potential to increase the number of patients receiving effective therapy while reducing unnecessary toxicity.
Authors
Angela Schab, Amanda Compadre, Rebecca Drexler, Megan Loeb, Kevin Rodriguez, Joshua Brill, Shariska Harrington, Carmen Sandoval, Brooke Sanders, Lindsay Kuroki, Carolyn McCourt, Andrea R. Hagemann, Premal Thaker, David Mutch, Matthew Powell, Violeta Serra, Ian S. Hagemann, Ann E. Walts, Beth Y. Karlan, Sandra Orsulic, Katherine Fuh, Lulu Sun, Priyanka Verma, Elena Lomonosova, Peinan Zhao, Dineo Khabele, Mary M. Mullen
Citation Information: J Clin Invest. 2025. https://doi.org/10.1172/JCI186915.
Abstract
BACKGROUND. Kidney stone disease (KSD) affects ~10% of adults, is heritable, and associated with mineral metabolic abnormalities. METHODS. Genetic variants and pathways increasing KSD risk via calcium and phosphate homeostasis were ascertained using genome-wide association analyses, region-specific Mendelian randomization (MR), and genetic colocalization. Utility of pathway modulation was estimated via drug-target MR, and effects of variants on calcium-sensing receptor (CaSR)-signaling characterized. RESULTS. Seventy-nine independent KSD-associated genetic signals at 71 loci were identified. MR identified three loci affecting KSD risk via increased serum calcium or decreased serum phosphate concentrations (odds ratios for genomic regions=4.30, 11.42, and 13.83 per 1 standard deviation alteration; p<5.6x10-10). Colocalization analyses defined putative, non-coding KSD-causing variants estimated to account for 11-19% of KSD cases in proximity to diacylglycerol kinase delta (DGKD), a CaSR-signalling partner; solute carrier family 34 member 1 (SLC34A1), a renal sodium-phosphate transporter; and cytochrome P450 family 24 subfamily A member 1 (CYP24A1), which degrades 1,25-dihydroxyvitamin D. Drug- target MR indicated that reducing serum calcium by 0.08mmol/L via CASR, DGKD, or CYP24A1, or increasing serum phosphate by 0.16mmol/L via SLC34A1 may reduce KSD relative risk by up to 90%. Furthermore, reduced DGKδ expression and KSD-associated DGKD missense variants impaired CaSR-signal transduction in vitro, which was ameliorated by cinacalcet, a positive CaSR-allosteric modulator. CONCLUSION. DGKD-, SLC34A1-, and CYP24A1-associated variants linked to reduced CaSR-signal transduction, increased urinary phosphate excretion, and impaired 1,25-dihydroxyvitamin D inactivation, respectively, are common causes of KSD. Genotyping patients with KSD may facilitate personalised KSD-risk stratification and targeted pharmacomodulation of associated pathways to prevent KSD.
Authors
Catherine E. Lovegrove, Michelle Goldsworthy, Jeremy Haley, Diane Smelser, Caroline Gorvin, Fadil M. Hannan, Anubha Mahajan, Mohnish Suri, Omid Sadeghi-Alavijeh, Shabbir H. Moochhala, Daniel P. Gale, David Carey, Michael V. Holmes, Dominic Furniss, Rajesh V. Thakker, Sarah A. Howles
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