BackgroundTripterygium wilfordii Hook F (TwHF), a traditional Chinese herb with immunosuppressive activity, has demonstrated clinical efficacy in the treatment of autoimmune diseases. However, the clinical application of TwHF has been greatly limited owing to its toxicity. Previously, we showed that the toxicity of TwHF can be reduced by liquorice processing, but the material basis for this reduced toxicity remains unclear.MethodsHere, we hypothesized that liquorice processing affects the components of TwHF. And LC-IT-TOF/MS together with plant metabolomics was applied to analyse the chemical composition of raw TwHF (Raw), TwHF combined with liquorice (Com), and TwHF processed by liquorice (Pro).ResultsAs a result, three differential compounds in TwHF, including triptolide, celastrol and wilforlide A, were tentatively identified. At the same time, we found that there were nine differential compounds from liquorice, including isoliquiritin, uralenin, coumestrol, liquiritigenin, schaftoside, glycyrrhizic acid, glyyunnanprosapogenin D, uralsaponin B and isolicoflavonol.ConclusionThese results will provide a basis for the scientific and rational use of TwHF processed by liquorice in the clinic.

Doravirine (DOR)-containing antiretroviral therapy (ART) has been recommended as first-line ART by China treatment guidelines since 2021. However, Real-world studies on DOR in China are scarce. We evaluated the real-world effectiveness of DOR-containing ART in Chinese people with HIV-1 (PWH), including treatment-naïve people regardless of viral load (VL) at baseline and treatment-experienced people regardless if they were virologic suppression (VS) or not. This was a retrospective, multicenter, observational study using medical chart review in seven hospitals, covering top-tier infectious disease hospitals across regions in China. All the participants who initiated DOR-containing ART during August 2021 and September 2023 were included and followed until September 2024. At baseline, higher proportions of the 352 participants were male (84.9

Background The extended survival of people living with HIV (PLWH) has shifted cancer burdens toward urological malignancies. PLWH exhibit unique clinical patterns, including younger age at diagnosis for renal cell carcinoma and more advanced stage at manifestations for prostate and bladder cancers, which are compounded by health care access inequities and human immunodeficiency virus (HIV)-specific mechanisms such as chronic immunosuppression. Methods A systematic search was conducted across five databases (Web of Science, PubMed, Cochrane Library, Embase, and Scopus) up to 1 July, 2025. Random-effects models were used to pool hazard ratios (HRs) and adjusted hazard ratios (aHRs). Publication bias was assessed using Egger's test, and sensitivity analyses were performed. Results Nine studies with 6,615,444 participants were included. The risk factors for mortality such as kidney cancer (aHR = 1.74; 95% CI: 1.11–2.75), prostate cancer (HR = 1.77; 95% CI: 1.60–1.96; aHR = 2.27; 95% CI: 1.77–2.90), and bladder cancer (aHR = 4.29; 95% CI: 1.08–17.03) were significantly higher for PLWH. The pooled unadjusted HR for kidney cancer was 1.66 (95% CI: 0.83–3.00) ,which did not reach statistical significance. Subgroup analyses for prostate cancer confirmed a consistent increase in mortality risk across different mortality types and follow-up durations. Conclusion HIV infection is significantly associated with increased mortality among patients with prostate cancer. For kidney cancer, limited data suggest an adverse prognostic role of HIV. For bladder cancer, the evidence remains preliminary but highlights the urgent need for dedicated investigations. These findings highlight the need to integrate urological cancer screening and tailored management into long-term HIV care. Future multicenter studies will be essential to strengthen the evidence, particularly for kidney and bladder cancers, and to clarify the roles of HIV-specific factors, tumor biology, and social determinants of health in optimizing precision medicine for this population.

CD39 exerts an inhibitory effect on tumour progression by impairing the cytotoxic capacity of natural killer (NK) cells against cancer cells. However, the impact of CD39 expression on the non-cytolytic functions of NK cells in treatment-naïve human immunodeficiency virus type 1 (HIV-1)-infected individuals remains poorly understood. In this study, thirty-four individuals with acute HIV-1 infection (AHI), thirty-eight with chronic HIV-1 infection (CHI), and twenty-four HIV-1-negative healthy controls (HC) were enrolled to explore the role of CD39 expression on NK cells in HIV-1 suppression at different infection stages. Flow cytometry was employed to analyze the immune phenotype and functional characteristics of NK cells. We found that CD39 expression on NK cells was significantly upregulated following HIV-1 infection, and its positive rate was positively associated with HIV-1 viral load in both AHI and CHI individuals. Compared with CD39- NK cells, CD39+ NK cells exhibited reduced activation; in AHI individuals, the activation level of CD39+ NK cells was positively associated with HIV-1 viral load but inversely correlated with CD4+ T-cell counts. In CHI individuals, the interleukin-10 (IL-10)-producing capacity of total NK cells, CD39+ NK cells, and CD39- NK cells was enhanced and positively correlated with HIV-1 viral load. Additionally, across the AHI and CHI groups, the overall IL-10-secreting ability of NK cells was positively correlated with the frequency of CD39+ NK cells. In both AHI and CHI individuals, CD39+ NK cells showed lower T-cell immunoglobulin and ITIM domain (TIGIT) expression than CD39- NK cells, while the CD39+TIGIT+ NK cell subset displayed significantly stronger IL-10-secreting capacity. POM-1, an inhibitor of CD39 ectonucleotidase activity, could enhance IL-10 secretion by NK cells in both HIV-1-infected individuals and the majority of healthy controls, but attenuate interferon-γ (IFN-γ) secretion by NK cells in HIV-1-infected individuals. In contrast, the CD39-blocking antibody A1 reduced IFN-γ secretion without affecting IL-10 secretion by NK cells in both HIV-1-infected individuals and healthy controls. Our findings reveal a novel CD39+ NK cell-associated mechanism that contributes to ineffective HIV-1 control, and suggest that CD39, alone or combined with TIGIT, may serve as a promising target to restore antiviral NK cell function in treatment-naïve individuals living with HIV-1.

OBJECTIVE:To systematically identify RING finger protein (RNF) biomarkers with diagnostic value in sepsis and to explore their potential as therapeutic targets. METHODS:Sepsis peripheral blood transcriptome datasets from Gene Expression Omnibus (GEO) were integrated. Sepsis-associated RNF genes were identified via differential expression analysis and weighted gene co-expression network analysis (WGCNA). Feature genes were selected using LASSO, SVM-RFE, and SHAP. Summary-data-based Mendelian randomization (SMR) assessed causality, and diagnostic performance was validated by receiver operating characteristic (ROC) curves in three independent cohorts. Single-cell RNA sequencing resolved cellular localization and perturbations. DrugReflector deep learning predicted repurposable drugs, molecular docking evaluated binding affinity, and PheWAS assessed target safety. RESULTS:A total of 13 sepsis-related RNF genes were identified, and three feature genes (ZFP36L2, RNF125, RNF175) were further selected. SMR showed that only elevated RNF175 expression significantly increased sepsis risk (OR = 1.267, 95% CI 1.002-1.603, P = 0.048). The diagnostic AUCs of RNF175 were 0.931, 0.776, and 0.835 in the training and two validation cohorts, respectively. Single-cell atlas revealed predominant RNF175 expression in T cells with significant upregulation in sepsis (P < 0.001). Deep learning predicted tadalafil as the top candidate, with a molecular docking binding energy of -9.072 kcal/mol for RNF175. PheWAS found no significant phenotype associations, indicating low off-target risk. CONCLUSIONS:RNF175 is an early sepsis biomarker with both diagnostic value and causal relevance, potentially acting through T-cell modulation. Tadalafil may be a pathway-targeted repurposable drug. This study provides new perspectives for precision medicine in sepsis.

OBJECTIVES:To investigate the impact of HIV-1 genotypes and population mobility on HIV-1 transmission in Guangzhou to obtain evidence for devising precision prevention and control strategies. METHODS:Demographic data and HIV-1 pol sequences were obtained from 6783 newly diagnosed people living with HIV (PLWH) in 2008-2020 in Guangzhou, including 24.0% local Guangzhou residents, 0.9% mobile Guangzhou residents, 56.4% local non-Guangzhou residents, and 18.6% mobile non-Guangzhou residents. HIV-1 genotypes were determined and molecular transmission networks were constructed using HIV-TRACE. Degree centrality and multinomial logistic regression were used to identify the key characteristics of the PLWH and risk factors of HIV-1 transmission. RESULTS:Among the PLWH, the dominated HIV-1 genotypes were CRF07_BC (39.6%), CRF01_AE (33.0%), and CRF55_01B (11.9%), and 43.3% of the PLWH formed 596 transmission clusters. Compared with subtype B, CRF01_AE (aOR=1.384, 95% CI: 1.072-1.798), CRF07_BC (aOR=2.462, 95% CI: 1.911-3.192), CRF55_01B (aOR=3.209, 95% CI: 2.424-4.271), and CRF59_01B (aOR=2.149, 95% CI: 1.437-3.219) were more likely to cluster. Population mobility was not associated with overall HIV-1 transmission, and local Guangzhou residents were more likely to be involved in CRF08_BC transmission (aOR=4.241, 95% CI: 1.494-12.790), whereas migrants had lower odds of transmitting CRF01_AE (aOR=0.740, 95% CI: 0.576-0.946) and subtype B (aOR=0.429, 95% CI: 0.182-0.922). The characteristics of high-risk individuals for HIV-1 transmission included local Guangzhou residents (aOR=1.390, 95% CI: 1.141-1.695), men (aOR=4.449, 95% CI: 2.402-8.242), MSM (aOR=1.783, 95% CI: 1.414-2.248), and infection with CRF07_BC (aOR=3.062, 95% CI: 1.963-4.777) or CRF55_01B (aOR=5.031, 95% CI: 3.159-8.014). CONCLUSIONS:Local Guangzhou residents, though accounting for only 24.9% in the PLWH, have a high risk of HIV-1 transmission, to which HIV-1 genotypes and MSM are also important contributors. Molecular network analysis provide important assistance for precision prevention and control of HIV-1 transmission.

e12646 Background: While estrogen receptor (ER)-positive/HER2-positive breast cancer generally demonstrates better long-term survival than ER-negative/HER2-positive disease, it shows significantly lower rates of pathological complete response (pCR) to standard neoadjuvant HER2-targeted therapies. Currently, the optimal ER positivity cutoff for stratifying patients remains undefined. Methods: We analyzed a retrospective cohort of 741 HER2-positive patients treated with neoadjuvant chemotherapy plus dual HER2 blockade (trastuzumab and pertuzumab). Receiver operating characteristic (ROC) analysis was used to define the optimal prognostic ER cutoff. Integrated multi-omics analysis (TCGA, SCAN-B) and CRISPR dependency screening (DepMap) were utilized to elucidate biological mechanisms and identify therapeutic vulnerabilities. Results: ROC analysis identified 50% ER positivity as the optimal threshold for stratifying response. In multivariate analysis, ER≥50% subgroup was characterized by activated estrogen signaling, downregulated cell cycle pathways, and predicted resistance to taxanes and antibody-drug conjugates (e.g., T-DXd). Conversely, CRISPR screening prioritized CDK4 as a top essential survival dependency specifically in ER-positive/HER2-positive models, suggesting functional addiction to the Cyclin D1-CDK4 axis. Conclusions: An ER cutoff of 50% optimally defines a distinct, chemo-resistant luminal subgroup within HER2-positive breast cancer. These findings support a precision medicine strategy integrating CDK4/6 inhibitors with endocrine and anti-HER2 therapies for patients with ER≥50% tumors.

Antiretroviral therapy (ART) has significantly extended the life expectancy of people with HIV (PWH), rendering population ageing and immunosenescence prominent clinical priorities. T-cell senescence is linked to mitochondrial dysfunction and drives age-related immune remodelling, yet how HIV infection and ageing jointly shape CD4+ and CD8+ T-cell immunophenotypes and mitochondrial remodelling remains unclear. This cross-sectional study included 61 PWH on suppressive ART for ≥ 12 months and 61 age- and sex-matched HIV-negative men who have sex with men, stratified into younger (≤ 35 years) and older (≥ 50 years) groups. Multiparameter flow cytometry was used to profile CD4+ and CD8+ T-cell differentiation, stemness, activation/exhaustion, and metabolic phenotypes, together with mitochondrial mass and membrane potential. We found that ageing and HIV infection were associated with T-cell remodelling, characterized by expanded late-differentiated phenotypes and reduced stem-like, homeostatic and costimulatory CD4+ and CD8+ T-cell subsets, as indicated by upregulated CD57 and CX3CR1 and downregulated CD45RA+CD31+, FOXO1, and CD28. Notably, younger PWH had an ageing-like CD4+ T-cell profile, with higher CD57, CX3CR1 and TIGIT expression than younger HIV-negative individuals. In contrast, HIV-related CD8+ T-cell perturbations (KLRG1, CXCR3, NKG2C and CD95) were more pronounced in older PWH. PWH exhibited increased mitochondrial mass and membrane potential in both total and senescent-like CD4+ and CD8+ T cells, particularly in CD8+ T cells from older PWH. In CD4+ T cells, KLRG1 and CX3CR1 expression correlated positively with age, and inversely with CD4+ T-cell counts and CD4/CD8 ratio. By contrast, FOXO1 expression in CD8+ T cells was inversely associated with age, late-differentiation markers, and ART duration in PWH. Overall, age is a major driver of T-cell immunosenescence, and HIV infection modulates and exacerbates these alterations. Mitochondrial stress, FOXO1 downregulation and immune network remodelling support a multifaceted model of HIV-associated immune ageing that may contribute to heterogeneous immune reconstitution in PWH, highlighting potential targets to mitigate immune ageing.

Background: MEK inhibitors have improved the management of neurofibromatosis type 1-associated plexiform neurofibromas (NF1-PNs), but the relationship between treatment continuity and post-discontinuation tumor behavior in routine practice remains unclear. Methods: We retrospectively analyzed 40 patients with NF1-associated PNs treated with selumetinib or luvometinib at a tertiary referral center. Patients were classified as discontinuation or no discontinuation according to treatment continuity during follow-up. Outcomes were assessed using a harmonized T0/T1/T2 framework. Pain was evaluated using the Numeric Rating Scale (NRS), and longitudinal tumor change was measured in the same predefined target lesion. Results: Nineteen patients discontinued treatment and 21 remained on treatment. Compared with the no-discontinuation group, the discontinuation group showed less favorable tumor trajectories, with smaller tumor shrinkage at T1 (P = 0.0107), tumor regrowth at T2 relative to baseline (P < 0.0001), and greater tumor rebound (P < 0.0001). In paired analyses within the discontinuation group, median tumor volume changed from − 5.0% at T1 to 5.0% at T2 (P = 0.0003). Pain outcomes were more heterogeneous, with no significant between-group difference in pain rebound. Among patients who discontinued treatment, cost-related interruption was the most frequent documented reason (10/19, 52.6%). Conclusions: In this real-world NF1-PN cohort, treatment discontinuation was common and was associated with less favorable tumor trajectories over time. The clearest post-discontinuation signal was observed in tumor rebound, whereas symptom changes were more heterogeneous. Cost-related interruption was the most frequent documented reason for discontinuation, suggesting that financial burden may represent an important practical barrier to sustained MEK inhibitor therapy.

BACKGROUND:Corrected QT (QTc) interval prolongation elevates fatal arrhythmia risk in people living with HIV (PLWH). Ainuovirine (ANV), a novel non-nucleoside reverse transcriptase inhibitor, demonstrates a favorable preclinical safety profile. This study evaluated ANV's effects on QTc interval and creatine kinase MB (CK-MB) levels in humans. METHODS:A pooled analysis was conducted using data from four phase 1 clinical studies: a single ascending dose (SAD), a food effect (FED), a multiple ascending dose (MAD), and a drug-drug interaction (DDI) study with lamivudine/tenofovir disoproxil fumarate (3TC/TDF). The analysis included healthy adults and treatment-naïve PLWH receiving ANV monotherapy or combination therapy. Concentration-QTc (C-QTc) modeling was performed using linear regression and linear mixed-effects (LME) models. The relationship between drug exposure (ANV, 3TC, TDF) and serum CK-MB levels was also assessed. RESULTS:Analysis of 85 participants with 838 time-matched C-QTc pairs revealed statistically insignificant negative slopes for ANV C-QTc relationships across all models. This indicates no significant ANV effect on QTc prolongation, consistent from subtherapeutic to supratherapeutic doses (75-300 mg). Bootstrapping validated model precision and reliability. ANV and lamivudine exposures showed no correlation with CK-MB elevation, while tenofovir disoproxil fumarate exposure demonstrated a positive correlation that remained clinically insignificant. CONCLUSIONS:ANV exhibits no statistically significant or clinically meaningful effect on QTc interval prolongation in healthy adults and treatment-naïve PLWH, even at supratherapeutic doses. CK-MB elevations were associated with tenofovir disoproxil fumarate exposure rather than ANV or lamivudine. These findings support the favorable cardiac safety profile of ANV-based regimens.

[This corrects the article DOI: 10.3389/fchem.2026.1770318.].

BackgroundGlobal and Chinese efforts still face significant gaps in achieving the first 95% of the “95-95-95” target, with persistently high and rising rates of late HIV diagnosis. This study evaluates RNA/DNA quantification, RNA qualitative, and ELISA assays to optimize HIV testing strategies.MethodsA prospective cross-sectional study evaluated 215 first-time HIV testers from June 2024 to May 2025. Using clinical diagnosis as the reference standard, we assessed four methods' sensitivity, specificity, and subgroup performance, with tandem testing strategies simulation for optimal detection.ResultsDNA quantitative detection demonstrated optimal performance with 100% sensitivity and specificity. RNA quantitative assay showed 99.02% sensitivity and 100% specificity, while ELISA achieved 99.02% sensitivity and 98.23% specificity. RNA qualitative testing exhibited 99.02% sensitivity but lower specificity (75.22%). ROC revealed superior diagnostic performance for DNA quantitative (AUC = 1.000) and RNA quantitative (AUC = 0.995) compared to RNA qualitative (AUC = 0.871). All methods maintained consistent sensitivity across CD4+ T cell levels. Simulation of tandem strategies identified ELISA combined with DNA quantitative testing as optimal (net sensitivity: 99.02%, net specificity: 100%, total tests: 318). For 18 WB-indeterminate samples, DNA/RNA quantitative methods achieved 100% diagnostic accuracy, outperforming RNA qualitative (94.44%) and ELISA (83.33%).ConclusionDNA quantitative detection shows high diagnostic value in initial HIV testing, overcoming challenges from undisclosed ART-induced RNA suppression and resolving WB-indeterminate misclassifications to reduce late diagnosis risks. This study supports Nucleic acid tests into diagnostic algorithms and validates the superior performance of ELISA screening followed by DNA confirmation, offering actionable strategies to shorten diagnostic delays and advance national AIDS control objectives.

Traditional treatments for lung cancer include surgery, radiotherapy, chemotherapy, and targeted therapies (such as Erlotinib, Gefitinib, and Crizotinib), as well as immunotherapy (such as Nivolumab and Pembrolizumab). However, these approaches face challenges such as drug resistance, limited efficacy, and significant side effects, making it difficult to improve long-term prognosis. Therefore, tumor vaccines, as a novel immunotherapy strategy, have become a focus of research, aiming to precisely activate anti-tumor immune responses and address the shortcomings of existing treatments. In recent years, mRNA vaccine technology has developed rapidly, especially following the successful application of COVID-19 vaccines, demonstrating its immense potential for rapid development and large-scale production. mRNA cancer vaccines induce durable anti-tumor immune responses and reshape the tumor microenvironment by delivering mRNA encoding tumor-specific antigens, enabling targeted therapy. Through the dual synergistic pathways of direct local modulation by the vector/encoded factors and secondary effects mediated by antigen-specific T-cell activation, the tumor microenvironment is reshaped, thereby inducing durable antitumor immune responses. Against this background, this review systematically evaluates the current status and prospects of mRNA vaccines in lung cancer treatment, with a focus on their progress in precisely modulating the tumor microenvironment, identifying novel tumor antigens, discovering immune biomarkers, and related clinical studies. Additionally, the review discusses the process optimization of lipid nanoparticle (LNP) delivery systems, aiming to provide theoretical support and practical guidance for the development of safe and effective therapeutic vaccine platforms for lung cancer.

Background:The extended survival of people living with human immunodeficiency virus (HIV) (PLWH) has shifted cancer burdens toward urological malignancies. PLWH exhibit unique clinical patterns, including a younger age at diagnosis for renal cell carcinoma and more advanced stage at presentation of prostate and bladder cancers, which are compounded by inequities in health care access and HIV-specific mechanisms such as chronic immunosuppression. Methods:A systematic search was conducted across five databases (Web of Science, PubMed, Cochrane Library, Embase, and Scopus) up to 1 July, 2025. Random-effects models were used to pool hazard ratios (HRs) and adjusted hazard ratios (aHRs). Publication bias was assessed using Egger's test, and sensitivity analyses were performed. Results:Nine studies with 6,615,444 participants were included. The risk factors for mortality such as kidney cancer (aHR = 1.74; 95% confidence interval [CI]: 1.11-2.75), prostate cancer (HR = 1.77; 95% CI: 1.60-1.96; aHR = 2.27; 95% CI: 1.77-2.90), and bladder cancer (aHR = 4.29; 95% CI: 1.08-17.03) were significantly higher for PLWH. The pooled unadjusted HR for kidney cancer was 1.66 (95% CI: 0.83-3.30), which did not reach statistical significance. Subgroup analyses for prostate cancer confirmed a consistent increase in mortality risk across different mortality types and follow-up durations. Conclusion:HIV infection is significantly associated with increased mortality among patients with prostate cancer. For kidney cancer, limited data suggest an adverse prognostic role of HIV. For bladder cancer, the evidence remains preliminary but highlights the urgent need for dedicated investigations. These findings highlight the need to integrate urological cancer screening and tailored management into long-term HIV care. Future multicenter studies will be essential to strengthen the evidence, particularly for kidney and bladder cancers, and to clarify the roles of HIV-specific factors, tumor biology, and social determinants of health in optimizing precision medicine for this population.

ObjectiveBoth B-cell- and T-cell-mediated immunity are crucial for the effective clearance of viral infection, but little is known about the dynamic characteristics of SARS-CoV-2-specific B-cell and T-cell responses in people living with HIV (PLWH) after a full course of inactivated SARS-CoV-2 vaccination.MethodsIn this study, fifty people living with HIV (PLWH) and thirty healthy controls (HCs) were enrolled to assess B-cell and T-cell responses at the day before the vaccination (T0), two weeks after the first dose (T1), two months after the first dose (T2), the day of the third dose (T3), one month after the third dose (T4), three months after the third dose (T5) and 12 months (T6) after the third dose.ResultsSARS-CoV-2-specific B-cell and T-cell responses were induced in people living with HIV (PLWH), and these responses lasted at least one year after the third vaccine dose. However, the peak frequencies of Spike-specific B-cell and T-cell responses in PLWH were lower than those in HIV-negative controls. In addition, the expansion of activated B cells, memory B cells and plasma cells after primary vaccination was observed, but the percentages of these cells were decreased at T6 and were comparable to those at T0. Additionally, the percentages of activated T cells, exhausted T cells and SARS-CoV-2-specific T cells with enhanced functional activity were increased following the administration of inactivated SARS-CoV-2 vaccine. In addition, PLWH had lower percentages of plasma cells, RBD-specific B cells, circulating Tfh (cTfh) cells and CD38+ cTfh cells, and the percentages of the latter two types of cells were positively correlated with the titer of neutralizing antibodies, indicating these differences may account for the weaker immune responses induced in PLWH.ConclusionThese data suggest that specific B-cell and T-cell responses could be sustained for at least one year after receiving the third vaccination. Our findings emphasize that the weak SARS-CoV-2-specific B-cell and T-cell responses induced in PLWH have implications for clinical decision-making and public health policy for PLWH with respect to SARS-CoV-2 infection.

ObjectiveThe role of natural killer (NK) cells, which mediate innate immunity, in the immune reconstitution of people living with HIV (PLWH) remains unclear. Our previous research indicated that early activation of CD56dimCD16dim/- NK cells plays an important role in the recovery of CD4+ T cells in immunological non-responders (INRs) after ART. This study mainly focuses on the profiles of cell receptors and their relative ligands for NK cells and CD4+ T cells exhibited on INRs and immunological responders (IRs) in order to analyze the impact of differential immune status on immune reconstitution in PLWH receiving ART.MethodsThis study included 66 PLWH who had been on ART for 4 years, comprising 32 INRs and 34 IRs. Using flow cytometry, we examined the expression of cell receptors and ligands for NK cells and CD4+ T cells in PBMCs, as well as the differentiation of CD4+ T cells.ResultsThe expression of NKG2D ligands, including MICA/B and ULBP2-5, on CD4+ T cells in INRs is elevated prior to ART. Further research found that the expression of CD95 on MICA/B+CD4+ T cells and ULBP2-5+CD4+ T cells was higher in INRs before ART compared to IRs. Simultaneously, the percentages of death receptor CD95 expression on MICA/B+CD4+ T cells and on ULBP2-5+CD4+ T cells before ART were negatively correlated with CD4+ T-cell counts and ΔCD4. Among the CD4+ T-cell subsets, an imbalance persists in the CD4+ Tcm and CD4+ Temra subsets in both INRs and IRs, before or after ART. CD4+ T cells exhibit elevated levels of activation, proliferation, exhaustion, and apoptosis prior to ART initiation. However, CD4+ T-cell activation and proliferation normalize post-ART, while apoptosis and exhaustion levels remain significantly elevated. Regardless of ART, the anti-apoptotic capacity of CD4+ T cells in INRs is still lower than that of IRs and healthy controls (HCs). Before ART, the frequency of CD31 expression on naive CD4+ T cells in INRs is lower than that in IRs and HCs. Following ART, the amounts of CD31+ Tn from CD4+ T cells remain impaired in both INRs and IRs compared to HCs.ConclusionThe upregulation of related ligands for the NKG2D receptor on CD4+ T cells in INRs is associated with increased susceptibility of CD4+ T cells to NK cell-mediated killing. CD95 may plays an important role in poor recovery of CD4+ T cells co-expressing NKG2D-related ligands. The imbalance in CD4+ Tcm and CD4+ Temra subset homeostasis and impaired CD31 expression on naive CD4+ T cells in INRs are associated with poor immune reconstitution outcomes.

INTRODUCTION:The relationship between serum cytokine levels and immunologic non-response in people living with HIV (PLWH) receiving antiretroviral therapy (ART) remains inadequately characterized. This study aimed to comprehensively characterize the serum cytokine profiles of men who have sex with men (MSM) living with HIV who exhibited different immunologic responses to ART. METHODS:We recruited MSM living with HIV and HIV-uninfected MSM (healthy controls, HC) in Guangzhou between June 1 to October 31, 2021. MSM living with HIV were classified as poor immunological responders (PIR, CD4+ T cell count <350 cells/μL) and good immunological responders (GIR, ≥ 350 cells/μL) after more than 24 months of ART. Blood samples were collected, and serum cytokines were quantified using Olink multiplex proximity extension assay (PEA). RESULTS:A total of 134 MSM were enrolled, including 44 HC, 52 GIR, and 38 PIR. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis revealed significant difference in the PI3K-AKT signaling pathways between GIR and PIR. Six candidate cytokine markers (PD-L1, FGF-19, CD244, CD8α, 4E-BP1, and CASP-8) were identified by least absolute shrinkage and selection operator (LASSO) regression for the construction of diagnostic models. The corresponding area under the curve (AUC) based on these six candidate markers was 0.844 (95 %CI: 0.647-1.000) in the support vector machine (SVM) model. Notably, PD-L1 and FGF-19 were identified as the top2 important cytokines for distinguishing between GIR and PIR based on LASSO regression, random forest (RF), and SVM analyses. Furthermore, PD-L1 and FGF-19 levels were negatively correlated with CD4+ T cell count (r = -0.34) and CD4+/CD8+ T cell ratio (r = -0.29), respectively. CONCLUSIONS:Distinct serum cytokine profiles were observed among PLWH with divergent immunologic responses, offering novel insights into the pathogenesis of immunologic non-response and identifying serum cytokines as promising therapeutic targets.

BACKGROUND:Randomized clinical trials (RCTs) in low/middle-income countries (LMICs) frequently produce evidence inconsistent with that conducted in high-income countries (HICs). This study aimed to compare RCT effect estimates in LMICs and HICs. METHODS:We identified RCTs from meta-analyses in six leading general medical journals and the Cochrane Database of Systematic Reviews between 2018 and 2023. Only RCTs that recruited participants after 2006 and used a negative control were included. Within each meta-analysis, RCTs sponsored by and enrolling participants in LMICs were designated as the exposed group, while those sponsored by and enrolling participants in HICs were the control group. Effect estimates were transformed into odds ratios (ORs); within each meta-analysis, ORs from LMICs and HICs were combined separately and compared as a ratio of ORs (RORs). RORs were combined across meta-analyses and subgrouped by patient-reported, investigator-assessed, and hard outcomes (e.g., mortality). An ROR larger than 1 indicated a larger OR from LMICs than from HICs. FINDINGS:1,005 RCTs (423 from LMICs and 582 from HICs) were identified from 140 meta-analyses. The overall ROR was 1.73 (95% confidence interval: 1.44-2.08). The RORs were 1.94 (1.45-2.61), 1.78 (1.35-2.35), and 1.04 (0.81-1.34) for patient-reported, investigator-assessed, and hard outcomes, respectively. The ROR decreased to 1.04 (0.87-1.24) when restricted to RCTs with a low risk of bias. CONCLUSIONS:Our study suggested that RCTs from LMICs may produce larger effect estimates than those from HICs, with the difference substantially smaller for RCTs with a low risk of bias, indicating that bias may contribute to the discrepancy. FUNDING:This work was supported by the Shenzhen Science and Technology Program, Shenzhen Institutes of Advanced Technology, and China Postdoctoral Science Foundation.

The association between gut microbial metabolites and immunologic non-response among people living with HIV (PLHIV) receiving antiretroviral therapy (ART) has not been well established. We aimed to characterize gut microbial metabolites among HIV-infected men who have sex with men (MSM) with different immunologic responses. We recruited HIV-infected MSM from Guangzhou Eighth People’s Hospital and HIV-uninfected MSM (healthy controls, HC) from a local MSM community-based organization in Guangzhou between June and October 2021. HIV-infected MSM were grouped into good immunological responders (GIR) (CD4 + T cell count ≥ 350 cells/μl) and poor immunological responders (PIR) (CD4 + T cell count < 350 cells/μl) after 24 months of ART treatment. Online questionnaires and stool samples were collected. Microbial metabolites in stool were obtained through ultra-performance liquid chromatography coupled to a tandem mass spectrometry (UPLC-MS/MS) system. Differential metabolites were identified and analyzed using the Kruskal–Wallis test, followed by pairwise comparisons with the Wilcoxon rank-sum test. The least absolute selection and shrinkage operator was used to select potential metabolites biomarkers. A total of 51 HC, 56 GIR, and 42 PIR were included. No statistically significant differences were observed in the median time since HIV diagnosis and ART duration between GIR and PIR. Among the 174 quantified metabolites, 81 significantly differed among HC, GIR, and PIR (P < 0.05). Among differential metabolites, indole-3-propionic acid significantly decreased from HC (11.39 nmol/g) and GIR (8.16 nmol/g) to PIR (6.50 nmol/g). The pathway analysis showed that tryptophan metabolism differed significantly between GIR and PIR (P < 0.05). Four potential metabolites biomarkers (dimethylglycine, cinnamic acid, 3-hydroxyisovaleric acid, and propionic acid) that distinguish GIR and PIR were identified, and the corresponding area under the curve based on potential biomarkers was 0.773 (95

Abstract Background Ainuovirine (ANV) is a novel non-nucleoside reverse transcriptase inhibitor (NNRTI) for treatment of HIV-1 infection. This study aimed to evaluate the safety, pharmacokinetics, and antiviral activity of short-term ANV monotherapy in antiretroviral treatment-naive adults with HIV-1.Table 1.Summary statistics of pharmacokinetic parameters of ainuovirine after single-dose and multi-doses in treatment-naïve HIV-infected adults. Data are expressed in median ± standard deviation (min, max); AUC0–t, area under the plasma concentration-time curve from time zero to time of the last quantifiable concentration; AUC0-t,ss, AUC0-t at steady state; AUC0-∞,ss, AUC from time zero to infinity at steady state; AUC0-τ, AUC at steady state; AUC_%Extrap, percentage of extrapolated AUC; Cmax, maximum plasma concentration; Cmax,ss, Cmax at steady state; Cmin,ss, minimum plasma concentration at steady state; Cav,ss, average steady state concentration; CLss/F, apparent clearance at steady state; DF, degree of fluctuation; MRT0-∞, mean retention time from time zero to infinity; Ra, accumulation ratio; Tmax, time to maximum plasma concentration; Tmax,ss, Tmax at steady state; T1/2z, plasma terminal half-life; Vz/F, apparent volume of distribution; λz, elimination rate constant. Methods A single-center, open-label, dose-ranging study was conducted among 28 treatment-naive adults with HIV-1. Participants received ainuovirine monotherapy, 75, 150, or 300 mg, once daily, for 10 days.Figure 1.Mean change from baseline in HIV RNA.Data are expressed in median±standard deviation. Results Baseline characteristics were similar across dose cohorts (75 mg, n=8; 150 mg, n=10; 300 mg, n=10). Across all dose cohorts, all adverse events were rated as mild to moderate in severity. No serious adverse event was reported. Pharmacokinetic parameters are shown in Table 1. ANV was readily absorbed, with the maximum concentration achieved at a median time of approximately 2-3 h after dosing. The ANV exposure (AUC and Cmax) increased slightly greater than the dose proportionality after single dose (day 1). Plasma ANV concentration reached the steady state at day 10 of dosing. Saturated Cmax,ss, AUCmax,ss, and C24h,ss were observed at 150 and 300 mg on day 10 after repeated dosing. Mean changes in HIV RNA from baseline (log10 copies/mL [90%CI]) were -1.73 [-1.90, -1.57], -1.72 [-1.87, -1.57], and -1.66 [-1.80, -1.51], respectively, on day 11 (Figure 1). Conclusion ANV demonstrated favorable safety and pharmacokinetics, and potent antiviral activity in treatment-naive adults with HIV-1.An once-daily dosing regimen of 150 mg was recommended for subsequent confirmatory efficacy trial. Disclosures Li Zhang, M.S., Jiangsu Aidea Pharmaceutical Co., Ltd.: Honoraria Xinming Yun, PhD, Jiangsu Aidea Pharmaceutical Co., Ltd.: Honoraria Hong Qin, MD, PhD, Jiangsu Aidea Pharmaceutical Co., Ltd: Honoraria