Short-chain fatty acids (SCFAs), key metabolites produced by gut microbiota, have neuroprotective effects in neurodegenerative diseases by modulating immune responses. However, their role in human immunodeficiency virus (HIV)-associated neurocognitive disorder (HAND) remains largely unexplored. We recruited HAND patients, HIV Control, and healthy controls (HC). Plasma SCFAs and SCFA-producing gut microbiota were quantified via gas chromatography-mass spectrometry and fecal metagenomic analysis. Inflammatory cytokine levels were measured using liquid chromatography. Receiver operating characteristic (ROC) curves were generated to evaluate the predictive accuracy of SCFAs for HAND. Plasma SCFAs were significantly reduced in HAND patients, correlating with a decrease in SCFA-producing gut bacteria, such as Prevotella and its related species. Reduced SCFAs were positively correlated with pro-inflammatory cytokines and cognitive impairment, while being negatively correlated with anti-inflammatory cytokines. ROC curve analysis demonstrated that several SCFAs exhibited strong predictive accuracy for HAND status. SCFAs may influence cognitive function by modulating inflammatory responses, and identifies plasma SCFAs as potential biomarkers and therapeutic targets for HAND. Further investigation is needed to delineate the mechanisms that SCFAs influence HAND pathology.

BackgroundThis study was the first to examine the association of baseline clinical factors with the rate of HBsAg clearance in a large retrospective cohort of Chinese patients with HIV/HBV coinfection treated with combination antiretroviral therapy (ART).MethodsOur retrospective cohort included 431 patients with HIV/HBV coinfection treated with TDF-containing ART. The median follow-up was 6.26 years. Logistic regression was used to investigate the association of baseline variables with HBsAg clearance, and Cox regression was used to investigate the association of baseline variables with time to HBsAg clearance.ResultsThe clearance rate of HBsAg in our study was 0.072 (95% CI 0.049~0.101). In the multivariate logistic regression, advanced age (OR=1.1, P=0.007), high CD4 cell count (OR=2.06, P=0.05), and HBeAg positivity (OR=8.00, P=0.009) were significantly associated with the rate of HBsAg clearance. The AUC of the model integrating the above three predictors was 0.811. Similar results were found in the multivariate Cox regression (HR = 1.09, P = 0.038 for age, HR = 1.05, P = 0.012 for CD4 count and HR = 7.00, P = 0.007 for HBeAg).ConclusionsLong-term TDF-containing ART can lead to HBsAg clearance of 7.2% in Chinese patients with HIV/HBV coinfection. Advanced age, high CD4 cell count, and positive HBeAg at baseline could be regarded as potential predictors and biological markers for HBsAg clearance in patients with HIV/HBV coinfection.

Background: T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibition motif domains (TIGIT), an inhibitory receptor expressed on T cells, plays a dysfunctional role in antiviral infection and antitumor activity. However, it is unknown whether TIGIT expression on T cells influences the immunological effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) inactivated vaccines.Methods: Forty-five people living with HIV (PLWH) on antiretroviral therapy (ART) for more than two years and 31 healthy controls (HCs), all received a third dose of a SARS-CoV-2 inactivated vaccine, were enrolled in this study. The amounts, activation, proportion of cell subsets, and magnitude of the SARS-CoV-2-specific immune response of TIGIT+CD4+ and TIGIT+CD8+ T cells were investigated before the third dose but 6 months after the second vaccine dose (0W), 4 weeks (4W) and 12 weeks (12W) after the third dose.Results: Compared to that in HCs, the frequency of TIGIT+ CD8+T cells in the peripheral blood of PLWH increased at 12W after the third dose of the inactivated vaccine, and the immune activation of TIGIT+CD8+ T cells also increased. A decrease in the ratio of both T na?ve (TN) and central memory (TCM) cells among TIGIT+CD8+T cells and an increase in the ratio of the effector memory (TEM) subpopulation were observed at 12W in PLWH. Interestingly, particularly at 12W, a higher proportion of TIGIT+CD8+ T cells expressing CD137 and CD69 simultaneously was observed in HCs than in PLWH based on the activation-induced marker assay. Compared with 0W, SARS-CoV-2-specific TIGIT+CD8+ T-cell responses in PLWH were not enhanced at 12W but were enhanced in HCs. Additionally, at all time points, the SARS-CoV-2-specific responses of TIGIT+CD8+ T cells in PLWH were significantly weaker than those of TIGIT-CD8+ T cells. However, in HCs, the difference in the SARS-CoV-2-specific responses induced between TIGIT+CD8+ T cells and TIGIT-CD8+ T cells was insignificant at 4W and 12W, except at 0W.Conclusions: TIGIT expression on CD8+ T cells may hinder the T-cell immune response to a booster dose of an inactivated SARS-CoV-2 vaccine, suggesting weakened resistance to SARS-CoV-2 infection, especially in PLWH. Furthermore, TIGIT may be used as a potential target to increase the production of SARS-CoV-2-specific CD8+ T cells, thereby enhancing the effectiveness of vaccination.

T follicular helper (Tfh) cells and their interactions with B cells within the germinal center play extensive roles in human immunodeficiency virus (HIV) pathology. However, their association with immune reconstitution during antiretroviral therapy (ART) is still unclear. The aim of this study was to determine the impact of Tfh and memory B cell function on T helper cell recovery in patients with acute or chronic HIV infection. A total of 100 HIV-infected individuals were enrolled in our study, classified into acute and chronic HIV infection groups (60 and 40, respectively), and subsequently classified into immunological responder (IR) and immunological nonresponder (INR) subgroups according to immune recovery outcomes after 96 weeks of ART. Liquid chromatography-mass spectrometry was used to quantify the temporal regulation patterns of B and CD4(+) T-cell profiles among patients, and flow cytometry was used to investigate certain subsets of B and T cells. Here we showed that the prevalence of Tfh cells in the T helper cell population correlated negatively with CD4(+) T-cell recovery. The proportion of CXCR3(-) Tfh cells in patients with acute or chronic infection was associated with CD4(+) T-cell count recovery, and the proportion of CD21(+) memory B cells at baseline was significantly higher in those with improved immune recovery outcomes. Universal proteomic dysregulation of B and CD4(+) T cells at baseline was detected in patients with acute infected and poor CD4(+) T-cell recovery. Proteomics analysis revealed distinct temporal regulation profiles of both T helper cells and B cells between IRs and INRs among patients with acute infection. Our results suggest that the functions of memory B cells in INRs are dysregulated at the early stage of ART, possibly through disruption of Tfh cell function. The frequency and function of Tfh cells and their subsets are potential predictors of poor immune recovery.

Although antiretroviral therapy (ART) can reduce the viral load in the plasma to undetectable levels in human immunodeficiency virus (HIV)-infected individuals, ART alone cannot completely eliminate HIV due to its integration into the host cell genome to form viral reservoirs. To achieve a functional cure for HIV infection, numerous preclinical and clinical studies are underway to develop innovative immunotherapies to eliminate HIV reservoirs in the absence of ART. Early studies have tested adoptive T-cell therapies in HIV-infected individuals, but their effectiveness was limited. In recent years, with the technological progress and great success of chimeric antigen receptor (CAR) therapy in the treatment of hematological malignancies, CAR therapy has gradually shown its advantages in the field of HIV infection. Many studies have identified a variety of HIV-specific CAR structures and types of cytolytic effector cells. Therefore, CAR therapy may be beneficial for enhancing HIV immunity, achieving HIV control, and eliminating HIV reservoirs, gradually becoming a promising strategy for achieving a functional HIV cure. In this review, we provide an overview of the design of anti-HIV CAR proteins, the cell types of anti-HIV CAR (including CAR T cells, CAR natural killer cells, and CAR-encoding hematopoietic stem/progenitor cells), the clinical application of CAR therapy in HIV infection, and the prospects and challenges in anti-HIV CAR therapy for maintaining viral suppression and eliminating HIV reservoirs.

Abstract. Over the past few years, the human virome and its complex interactions with microbial communities and the immune system have gained recognition as a crucial factor in human health. Individuals with compromised immune function encounter distinctive challenges due to their heightened vulnerability to a diverse range of infectious diseases. This review aims to comprehensively explore and analyze the growing evidence regarding the role of the virome in immunocompromised disease status. By surveying the latest literature, we present a detailed overview of virome alterations observed in various immunodeficiency conditions. We then delve into the influence and mechanisms of these virome changes on the pathogenesis of specific diseases in immunocompromised individuals. Furthermore, this review explores the clinical relevance of virome studies in the context of immunodeficiency, highlighting the potential diagnostic and therapeutic gains from a better understanding of virome contributions to disease manifestations.

Background::Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine can induce a potent cellular and humoral immune response to protect against SARS-CoV-2 infection. However, it was unknown whether SARS-CoV-2 vaccination can induce effective natural killer (NK) cell response in people living with human immunodeficiency virus (PLWH) and healthy individuals.Methods::Forty-seven PLWH and thirty healthy controls (HCs) inoculated with SARS-CoV-2 inactivated vaccine were enrolled from Beijing Youan Hospital in this study. The effect of SARS-CoV-2 vaccine on NK cell frequency, phenotype, and function in PLWH and HCs was evaluated by flow cytometry, and the response of NK cells to SARS-CoV-2 Omicron Spike (SARS-2-OS) protein stimulation was also evaluated.Results::SARS-CoV-2 vaccine inoculation elicited activation and degranulation of NK cells in PLWH, which peaked at 2 weeks and then decreased to a minimum at 12 weeks after the third dose of vaccine. However, in vitro stimulation of the corresponding peripheral blood monocular cells from PLWH with SARS-2-OS protein did not upregulate the expression of the aforementioned markers. Additionally, the frequencies of NK cells expressing the activation markers CD25 and CD69 in PLWH were significantly lower than those in HCs at 0, 4 and 12 weeks, but the percentage of CD16 + NK cells in PLWH was significantly higher than that in HCs at 2, 4 and 12 weeks after the third dose of vaccine. Interestingly, the frequency of CD16 + NK cells was significantly negatively correlated with the proportion of CD107a + NK cells in PLWH at each time point after the third dose. Similarly, this phenomenon was also observed in HCs at 0, 2, and 4 weeks after the third dose. Finally, regardless of whether NK cells were stimulated with SARS-2-OS or not, we did not observe any differences in the expression of NK cell degranulation markers between PLWH and HCs. Conclusions::SARS-CoV-2 vaccine elicited activation and degranulation of NK cells, indicating that the inoculation of SARS-CoV-2 vaccine enhances NK cell immune response.

Background Sengers syndrome characterized by hypertrophic cardiomyopathy is an extremely rare genetic disorder. Sengers syndrome associated with left ventricular non-compaction (LVNC) has not been described. Methods Genetic testing was used to identify candidate AGK variants in the proband. The predicted molecular structures were constructed by protein modeling. Exon skipping caused by the identified splicing mutations was verified by in silico analyses and in vitro assays. The genotypic and phenotypic features of patients with AGK splicing mutations were extracted by a systematic review. Results The proband was characterized by Sengers syndrome and LVNC and caused by a novel compound heterozygous AGK splicing mutation. This compound mutation simultaneously perturbed the protein sequences and spatial conformation of the acylglycerol kinase protein. In silico and in vitro analyses demonstrated skipping of exons 7 and 8 and premature truncation as a result of exon 8 skipping. The systematic review indicated that patients with an AGK splicing mutation may have milder phenotypes of Sengers syndrome. Conclusions The genotypic and phenotypic spectrums of Sengers syndrome have been expanded, which will provide essential information for genetic counseling. The molecular mechanism in AGK mutations can offer insights into the potential targets for treatment. Impact First description of a child with Sengers syndrome and left ventricular non-compaction cardiomyopathy. A novel pathogenic compound heterozygous splicing mutation in AGK for Sengers syndrome was identified. The identified mutations led to exons skipping by in silico analyses and in vitro assays.

Renal cell carcinoma (RCC), one of the most common genitourinary tumors, is induced by many factors, primarily smoking, obesity, and hypertension. As a non-acquired immunodeficiency syndrome (AIDS)-defining cancer, human immunodeficiency virus (HIV) may also play a critical role in the incidence and progression of RCC. It is evident that individuals who are infected with HIV are more likely than the general population to develop RCC. The age of RCC diagnosis among HIV-positive patients is younger than among HIV-negative individuals. However, many other characteristics remain unknown. With the increase in RCC incidence among HIV-infected patients, more research is being conducted to discover the relationship between RCC and HIV, especially with regard to HIV-induced immunodeficiency, diagnosis, and treatment. Unexpectedly, the majority of the literature suggests that there is no relationship between RCC and HIV-induced immunodeficiency. Nonetheless, differences in pathology, symptoms, or treatment in HIV-positive patients diagnosed with RCC are a focus. In this review, we summarize the association of RCC with HIV in terms of epidemiology, risk factors, diagnosis, and treatment.

•Albuvirtide (ABT) is a novel long-acting HIV fusion inhibitor.•ABT combined with LPV/r was non-inferior to LPV/r based three-drug regimen.•ABT combined with LPV/r showed a good safety profile.•ABT combined with LPV/r showed a trend of improvement in renal function.•ABT might be an interesting alternative option for HIV treatment and prevention.

目的 观察肥厚型心肌病(HCM)致病基因突变导致同一位点氨基酸不同改变的临床表型变化特点,为遗传型-表型关系研究积累数据.方法 在529例HCM患者以及307名健康对照者中进行β-肌球蛋白重链基因(MYH7)目标区域靶向捕获再测序筛查,发现的基因变异性Sanger法测序验证..结果 在1例HCM患者中首次发现MYH7基因29号外显子第4145位碱基由G转换为A,结果导致1382位的精氨酸(Arg,R)转变为谷氨酰胺(Gin,Q),另1例HCM患者,29号外显子第4144位碱基由C转换为T,结果导致1382位的精氨酸(Arg,R)转变为色氨酸(Trp,W),正常对照组相同位置1382位表达为精氨酸(Arg,R).MYH71382位氨基酸发生改变的两例HCM患者临床表型均为肥厚型梗阻性心肌病,并且均在住院期间接受了经皮室间隔心肌消融术治疗,长期随访预后良好.结论 首次在中国人HCM患者中发现MYH7基因Arg1382Gln突变,该位点氨基酸发生不同改变后具有相似的临床表型,表现为肥厚型梗阻性心肌病、经室间隔心肌消融术治疗效果好.提示一旦发现该位点基因突变就有可能实现临床表型预测.

目的 观察比较携带MYH7基因突变和携带MYBPC3基因突变的肥厚型心肌病(HCM)患者临床表型及预后特点.方法 回顾性分析在阜外医院就诊的203例肥厚型心肌病患者的临床资料,并对其进行随访的结果进行分析.结果 携带MYH7突变的HCM患者入组年龄(42.4±14.8 vs.49.8±14.0,P=0.0003)和确诊年龄(39.4±15.1 vs.46.8±14.3.P=0.0005)较携带MYBPC3突变的患者轻,梗阻发生率(53.6％ vs.29.0％,P=0.005)较携带MYBPC3突变患者高.在随访期间,携带MYBPC3突变的患者全因死亡14例,其中心血管死亡12例.携带MYH7突变患者全因死亡10例,其中心血管死亡9例.统计学显示两者全因死亡比例(P=0.27)和心血管死亡比例(P=0.25)无显著差异.结论 携带MYH7突变的HCM患者确诊年龄较轻,梗阻发生率较高,预后分析全因死亡率和心血管死亡率事件没有显著性差异.

BackgroundElevated high‐sensitivity C‐reactive protein (hsCRP) has been associated with increased risks of adverse outcomes of various cardiovascular diseases. The relationship between hsCRP and the prognosis of hypertrophic cardiomyopathy remains to be evaluated. Methods and ResultsThe study used an observational cohort methodology. A total of 490 patients were enrolled in the Fuwai Hospital from 2001 to 2011 and were followed for 3.7±2.0 years. According to the risk category of hsCRP, subjects in the high hsCRP group (>3.0 mg/L) had a higher risk of developing adverse events than the low hsCRP group (<1.0 mg/L): cardiovascular death (adjusted hazard ratios[HR] 5.41, 95% CI 1.96–14.93, P=0.001), all‐cause mortality (adjusted HR 4.78, 95% CI 1.99–11.47, P<0.001), sudden cardiac death (adjusted HR 11.29, 95% CI 1.38–92.20, P=0.024), and heart failure–related death (adjusted HR 4.38, 95% CI 1.15–16.60, P=0.030). Similarly, the continuous variable of hsCRP was also an independent predictor for adverse outcomes: cardiovascular death (adjusted HR 1.15, 95% CI 1.06–1.25, P=0.001), all‐cause mortality (adjusted HR 1.17, 95% CI 1.09–1.26, P<0.001), sudden cardiac death (adjusted HR 1.20, 95% CI 1.06–1.36, P=0.003), and heart failure–related death (adjusted HR 1.15, 95% CI 1.02–1.30, P=0.020). ConclusionsOur results indicate that elevated plasma hsCRP is associated with increased risk for adverse outcomes in patients with hypertrophic cardiomyopathy.

Objective To evaluate the correlation between functional domains of MYH7 mutations and clinical expressions in patients with hypertrophic cardiomyopathy (HCM).Methods MYH7 genotype-positive patients from previous studies were included.According the genotype of MYH7 mutations,the patients were separated into 3 groups:1) those only carrying one single mutation in the head or neck region of cardiac β-myosin heavy chain;2) those only carrying one single mutation in the a-helical coiled-coil tail region;and 3) those carrying more than one MYH7 mutation,including MYH7 compound mutations or mutation in other sarcomere genes.The baseline clinical characteristics and outcomes were analyzed.Results In total of 86 mutations were identified in 110 patients with HCM,most of which (84,97.7％) were missense.Among the identified mutaitons,41 (47.7％) located in the head region,24 (27.9) in the neck region and 21 (24.4％) in the a-helical coiled-coil tail region of cardiac β-myosin heavy chain.Among the MYH7 genotype-positive patients,23 (20.9％) carried compound MYH7 mutations or another mutation in other sarcomere genes.There were no significant differences were observed among three groups of patients with HCM.During a follow-pu of 5.3±3.8 years,the risk for cardiovascular deaths and all-cause mortality were comparable between patients with mutations in head/neck regions and tail regions.However,MYH7 genotype-positive patients with multiple mutations had increased risk for cardiovascular deaths (adjusted HR 7.27,95％ CI 1.68-31.36,P=0.008) and all-cause mortality (adjusted HR 7.56,95％ CI 1.97-29.09,P=0.003) than those only carrying one MYH7 mutations.Conclusion There was no relationship between functional domains of MYH7 mutations and the clinical expression and outcomes of patients with HCM.MYH7 genotype-positive patients with multiple mutations had increased risk for malignant prognosis.

Objective To identify the disease-causing gene mutations and to reveal the relationship between the genotype and the phenotype in Chinese patients with hypertrophic cardiomyopathy(HCM).Methods Five hundred and twenty-nine unrelated patients with HCM and 370 controls were enrolled in this study.The full encoding exons and flanking sequences of the cardiac myosin binding protein C gene(MYBPC3)were amplified with PCR and the products were sequenced.Results A nonsense mutation c.2526C＞G was identified in exon 25 of MYBPC3 gene in three HCM patients,which resulted a Tyrosine(Y) to Nonsense(Stop) exchange at amino acid residue 842(Tyr842Ter).The clinical phenotypes of the three patients were the same (non-obstructive HCM with atrial fibrillation).The 370 controls were normal in the genetic test.Conclusions The Tyr842Ter mutation in MYBPC3 gene was a benign mutation in Chinese patients with HCM,and had a good prognosis.

Background: Titin-truncating variants (TTNtv) have been detected in a variety of cardiomyopathies and represent the most common cause of dilated cardiomyopathy. However, their significance in hypertrophic cardiomyopathy (HCM) is still unclear.Methods: The titin gene (TTN) was sequenced for truncating variants in a cohort of 529 Chinese patients with HCM and 307 healthy controls. Baseline and follow-up clinical data ( for 4.7 +/- 3.2 years) from these patients were obtained.Results: We identified 13 and 8 TTNtv in patients with HCM (13 of 529 [2.5%]) and controls (8 of 307 [2.6%]), respectively. The prevalence of TTNtv in patients with HCM and in healthy controls was comparable (P = 0.895). There were no significant differences in baseline characteristics between patients with and those without TTNtv. However, during follow-up, patients with TTNtv (3 of 13 [23.1%]) were more likely to experience cardiovascular death compared with those without TTNtv (39 of 516 [7.6%]) [adjusted hazard ratio, 6.88; 95% confidence interval, 2.04-23.20; P = 0.002).Conclusions: Our study suggests that TTNtv might be a genetic modifier of HCM and confer an increased risk for cardiovascular death.

Background: Takayasu arteritis (TA) is a rare inflammatory arteriopathy of unknown etiology. The aim of this study was to investigate the genetic susceptibility to TA in a Chinese population. Methods: Four single nucleotide polymorphisms (SNPs) those locate in the IL12B region (rs56167332), the MLX region (rs665268), the FCGR2A/FCGR3A locus (rs10919543), and the HLA-B/MICA locus (rs12524487), associated with TA in different population, were genotyped in 123 Chinese TA patients and 147 healthy controls from January 2013 to August 2014. A Chi-square test was used to test for genotype/allele frequencies variants. Results: Among the four SNPs, rs10919543 was found to be significantly associated with TA in the studied population. The GG genotype of rs10919543 at the FCGR2A/FCGR3A locus is a high risk factor (odds ratio [OR] = 6.532, 95% confidence interval [CI] = 2.402 − 17.763, P < 0.001) for TA. Among TA patients, the level of eosinophil granulocytes (Eos) in the peripheral blood was observed to be higher in the GG group of rs10919543 (n = 23, Eos = 0.11 [0.08, 0.17] ×109/L) than the GA + AA group (n = 100, Eos = 0.08 [0.05, 0.13] ×109/L, P = 0.028). No correlation between the genotypes of the other three SNPs and TA patients was observed. Conclusions: Our findings revealed unique genetic pattern in Chinese TA patients that may be partly responsible for the higher risk of TA in this population. FCGR2A/FCGR3A-related immune disorder might contribute to the etiology of TA.

Andersen-Tawil syndrome (ATS) is an autosomal dominant, multisystem channelopathy characterized by periodic paralysis, ventricular arrhythmias and distinctive dysmorphic facial or skeletal features. The disorder displays marked intrafamilial variability and incomplete penetrance. Myasthenia gravis (MG) is an autoimmune disorder that demonstrates progressive fatigability, in which the nicotinic acetylcholine receptor (AChR) at neuromuscular junctions is the primary autoantigen. The present study reports a rare case of a 31-year-old woman with a history of morbid obesity and periodic weakness, who presented with hemodynamic instability, cardiogenic shock and facial anomalies. Laboratory results revealed hypokalemia and an elevated anti-AChR antibody expression levels. Electrocardiography demonstrated prolonged QT-interval, ST-elevation, and subsequent third-degree atrioventricular block. Neurological examination revealed bilateral ptosis, horizontal diplopia, dysarthria and generalized weakness. No mutations in the potassium channel inwardly rectifying subfamily J member 2 gene were detected in the present case. The patient was treated with oral potassium supplementation and an acetylcholinesterase inhibitor (pyridostigmine), after which the symptoms were improved. To the best of our knowledge, the present case report was the first to describe concomitant presentation of both ATS and MG, which represents a diagnostic and therapeutic challenge.