Reservoir of human immunodeficiency virus in the brain:New insights into the role of T cells

Human immunodeficiency virus(HIV)infection of the central nervous system(CNS)has attracted significant attention because it contributes to severe complications of acquired immunodeficiency syndrome(AIDS)and seriously impairs the life quality of infected patients.In this review,we briefly describe the latent infection of HIV in CNS and focus on the role of the important immune cells,such as T cells,in the formation and maintenance of the HIV reservoir in CNS.This review explores the mechanisms by which T cells enter CNS and establish latent infection of HIV in the CNS.In conclusion,we summarize the role of these cells in the interaction between HIV and CNS.With our better understanding of the underlying mechanisms,we propose future directions for the development of novel strategies to eliminate HIV reservoirs in the CNS based on cellular components.

Socioeconomic Impact and Response Strategies to the Multifaceted Respiratory Illness Outbreak in Northern China:Beyond Influenza A and Mycoplasma Pneumoniae

This study examines the socioeconomic and public health effects of a recent respiratory illness outbreak in northern China,focusing on Beijing following the lifting of coronavirus disease 2019(COVID-19)restrictions.It analyzes the implications of increased influenza A(H3N2)and Mycoplasma pneumoniae cases on urban health systems and economic structures.This mixed-methods study integrated a review of academic and governmental literature,a quantitative analysis of public health data,and a qualitative assessment of response strategies.Findings indicate a significant increase in respiratory illnesses in late 2023,prompting a proactive response from health authorities that involved expanded hospital capacity and intensified surveillance.Challenges,including resource limitations and public health fatigue,persisted,affecting response efficacy.Effective outbreak management was achieved through immediate health responses,although the event highlighted the need for improved infrastructure,surveillance,and policy frameworks.Recommendations emphasize the importance of international collaboration and comprehensive preparedness plans to strengthen global health security for future epidemics.

Clinical efficacy and computed tomography diagnostic value of bedaquiline-containing regimens in the treatment of drug-resistant pulmonary tuberculosis

Objective:This study investigated the clinical efficacy of bedaquilinecontaining regimens in the treatment of drug-resistant pulmonary tuberculosis and the diagnostic value of computed tomography(CT).Methods:We retrospectively analyzed the clinical diagnosis,treatment,and CT imaging data of patients with drug-resistant pulmonary tuberculosis treated in Wenzhou Central Hospital from 1 January to 31 December 2022.According to whether the treatment regimen contained bedaquiline,the patients were divided into an observation group(bedaquiline tablets t background regimen)and a control group(background regimen).The clinical efficacy and pulmonary CT changes before and after treatment were analyzed in both groups.Results:After 24 weeks of treatment,there was no statistically significant difference in the white blood cell count or concentrations of hemoglobin,alanine aminotransferase,serum albumin,or creatinine between the two groups(t=0.71,0.93,0.05,0.18,and 0.08,respectively;p>0.05).After 4,8,and 12 weeks of treatment,there was no statistically significant difference in the sputum culture-negative conversion rate between the two groups(χ^(2)=2.67,0.48,and 1.82,respectively;p>0.05).At 24 weeks of treatment,the sputum culture-negative conversion rate in the observation group reached 100%,which was significantly higher than that in the control group(χ^(2)=3.97,p<0.05).The effective absorption rates on chest imaging in the two groups of patients at 12 weeks were 83.33% and 57.89%,respectively.At 24 weeks of treatment,the effective absorption rates were 88.00% and 65.85% in the two groups,with a statistically significant difference(χ^(2)=3.98;p<0.05).There were significant differences in cavity absorption at 24 weeks(χ^(2)=4.33,p<0.05)and 48 weeks after treatment(χ^(2)=10.63,p<0.05).Conclusion:The addition of bedaquiline to the background regimen improved the sputum culture-negative conversion rate and chest imaging effective rate.Patients achieved good results at the end of the 24-week treatment period.

Evaluation of Epstein-Barr Virus Salivary Shedding in HIV/AIDS Patients and HAART Use: A Retrospective Cohort Study

Little data is available on the evaluation of the occurrence rates of Epstein-Barr virus(EBV) in saliva and relationship with highly active antiretroviral therapy(HAART) use in HIV/AIDS patients in China. We conducted a retrospective cohort study of EBV serological tests for HIV/AIDS patients who were treated in the hospitals for infectious diseases in Wuxi and Shanghai, China from May 2016 to April 2017. The EBV-seropositive samples were identified by ELISA. EBV-specific primers and probes were used for the quantitative detection of viral DNA from saliva via quantitative real-time polymerase chain reaction. CD4 cell counts of the HIV/AIDS patients were detected by a flow cytometry. A total of 372 HIV/AIDS patients were ultimately selected and categorized for this retrospective cohort study. For EBV IgG and IgM, the HIV/AIDS HAART use(H) and non-HAART use(NH) groups had significantly higher seropositive rates than the HIV-negative control group. The HIV/AIDS(NH) group had the highest seropositive rate(IgG, 94.27%; IgM, 68.98%) and the highest incidence of EBV reactivation or infection. For salivary EBV DNA-positive rates and quantities, the HIV/AIDS(H)(73.69%) and the HIV/AIDS(NH)(100%) groups showed significantly higher values than the HIV-negative control group(35.79%,[ twofold). Further, the salivary EBV DNA-negative population had significantly higher CD4 cell counts than the EBV DNA-positive population in the HIV/AIDS(H) group and the HIV/AIDS(NH) groups. Thus, HAART use is beneficial in decreasing the EBV salivary shedding in HIV/AIDS patients and indirectly decreases EBV transmission risk.

Hymecromone:a clinical prescription hyaluronan inhibitor for efficiently blocking COVID-19 progression

Currently,there is no effective drugs for treating clinically COVID-19 except dexamethasone.We previously revealed that human identical sequences of SARS-CoV-2 promote the COVID-19 progression by upregulating hyaluronic acid(HA).As the inhibitor of HA synthesis,hymecromone is an approved prescription drug used for treating biliary spasm.Here,we aimed to investigate the relation between HA and COVID-19,and evaluate the therapeutic effects of hymecromone on COVID-19.Firstly,HA was closely relevant to clinical parameters,including lymphocytes(n=158;r=−0.50;P<0.0001),C-reactive protein(n=156;r=0.55;P<0.0001),D-dimer(n=154;r=0.38;P<0.0001),and fibrinogen(n=152;r=0.37;P<0.0001),as well as the mass(n=78;r=0.43;P<0.0001)and volume(n=78;r=0.41;P=0.0002)of ground-glass opacity,the mass(n=78;r=0.48;P<0.0001)and volume(n=78;r=0.47;P<0.0001)of consolidation in patient with low level of hyaluronan(HA<48.43 ng/mL).Furthermore,hyaluronan could directly cause mouse pulmonary lesions.Besides,hymecromone remarkably reduced HA via downregulating HAS2/HAS3 expression.Moreover,89%patients with hymecromone treatment had pulmonary lesion absorption while only 42%patients in control group had pulmonary lesion absorption(P<0.0001).In addition,lymphocytes recovered more quickly in hymecromone-treated patients(n=8)than control group(n=5)(P<0.05).These findings suggest that hymecromone is a promising drug for COVID-19 and deserves our further efforts to determine its effect in a larger cohort.

Recycle-Friendly Aluminum Alloy Sheets for Automotive Applications Based on Hemming

Unavoidably,Fe impurities are mixed into Al alloys during recycling of aluminum automotive parts.High Fe content recyclefriendly aluminum alloy sheets(RASs)are discussed in terms of their applications to car body parts and closures.RASs have advantages,such as they are low cost and light weight,they require less energy to process,and they reduce emissions when used in vehicles.The hemming ability of RASs was investigated through various quenching rates and hot-rolling reduction rates.The hemming factor(HF)values of low Fe content samples(0.1 and 0.3 wt%Fe content)were 2 and 3.The hemming ability of samples with an Fe content of 0.5 wt%was unacceptable for applications to automotive outer closures(i.e.,HF values of 4 and 5).The HF values changed from 3 to 5 for even higher Fe content samples(0.8 wt%Fe),depending on the quenching and hot-rolling reduction rates.Lower quenching(air quenching)and lower hot-rolling reduction rates(6-pass hot rolling)both improved the hemming ability of the high Fe content samples.A low-cost and recycle-friendly aluminum alloy automotive sheet from end-of-life vehicles is presented,and its hemming properties are characterized.

Cost-effectiveness evaluation of rapid initiation of antiretroviral therapy based on decision-tree Markov model

To the Editor:Human immunodeficiency virus(HIV)type 1 infection remains a serious and intractable public health problem worldwide.In 2020,there were 37.7 million surviving individuals with HIV infection worldwide and 680,000 HIV-related deaths reported by the Joint United Nations Programme on HIV/acquired immune deficiency syndrome(AIDS)(UNAIDS).

The incidence of liver abnormalities is higher in inactive hepatitis B virus carriers with influenza A infection

1INTRODUCTION China is still at a high risk of hepatitis B virus(HBV)infection and has a large number of inactive HBV carriers(ICs)[1].Chronic hepatitis B viral infection is a global problem,which commonly progresses to liver cirrhosis[2],hepatocellular carcinoma[3],and liver diseaserelated death[4].

Systemic and dynamic immune landscape of Omicron-infected subjects treated with Lianhua Qingwen capsules

To the Editor:The COVID-19 has represented an unexpected global public health challenge due to the profound immune evasion and transmission capabilities of the responsible virus SARS-CoV-21,being in great short of effective prophylactic and curative methods.Lianhua Qingwen(LHQW)capsule,a traditional Chinese medicine(TCM)formula,is officially included in China's COVID-19 treatment guidelines and has shown antiviral activity in vitro and in vivo.Recent clinical trials have shown that LHQW can alleviate symptoms and accelerate recovery in Omicron-infected patients2.The immune pathology of COVID-19 involves a complex interplay between virus-induced injuries and multifactorial immune responses.However,a comprehensive analysis of the immunological basis of LHQW's effects in Omicron-infected subjects is still lacking.

Anti-PD-L1 antibody ASC22 in combination with a histone deacetylase inhibitor chidamide as a “shock and kill” strategy for ART-free virological control: a phase Ⅱ single-arm study

The combination of ASC22, an anti-PD-L1 antibody potentially enhancing HIV-specific immunity and chidamide, a HIV latency reversal agent, may serve as a strategy for antiretroviral therapy-free virological control for HIV. People living with HIV, having achieved virological suppression, were enrolled to receive ASC22 and chidamide treatment in addition to their antiretroviral therapy. Participants were monitored over 24 weeks to measure changes in viral dynamics and the function of HIV-specific CD8^(+) T cells (NCT05129189). 15 participants completed the study. At week 8, CA HIV RNA levels showed a significant increase from baseline, and the values returned to baseline after discontinuing ASC22 and chidamide. The total HIV DNA was only transiently increased at week 4 (P = 0.014). In contrast, integrated HIV DNA did not significantly differ from baseline. Increases in the proportions of effector memory CD4^(+) and CD8^(+) T cells (TEM) were observed from baseline to week 24 (P = 0.034 and P = 0.002, respectively). The combination treatment did not succeed in enhancing the function of HIV Gag/Pol- specific CD8^(+) T cells. Nevertheless, at week 8, a negative correlation was identified between the proportions of HIV Gag-specific TEM cells and alterations in integrated DNA in the T cell function improved group (P = 0.042 and P = 0.034, respectively). Nine adverse events were solicited, all of which were graded 1 and resolved spontaneously. The combined treatment of ASC22 and chidamide was demonstrated to be well-tolerated and effective in activating latent HIV reservoirs. Further investigations are warranted in the context of analytic treatment interruption.

Asialoglycoprotein receptor 1 promotes SARS-CoV-2 infection of human normal hepatocytes

Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)causes multi-organ damage,which includes hepatic dysfunction,as observed in over 50%of COVID-19 patients.Angiotensin I converting enzyme(peptidyl-dipeptidase A)2(ACE2)is the primary receptor for SARS-CoV-2 entry into host cells,and studies have shown the presence of intracellular virus particles in human hepatocytes that express ACE2,but at extremely low levels.Consequently,we asked if hepatocytes might express receptors other than ACE2 capable of promoting the entry of SARS-CoV-2 into cells.To address this question,we performed a genome-wide CRISPR-Cas9 activation library screening and found that Asialoglycoprotein receptor 1(ASGR1)promoted SARS-CoV-2 pseudovirus infection of HeLa cells.In Huh-7 cells,simultaneous knockout of ACE2 and ASGR1 prevented SARS-CoV-2 pseudovirus infection.In the immortalized THLE-2 hepatocyte cell line and primary hepatic parenchymal cells,both of which barely expressed ACE2,SARSCoV-2 pseudovirus could successfully establish an infection.However,after treatment with ASGR1 antibody or siRNA targeting ASGR1,the infection rate significantly dropped,suggesting that SARS-CoV-2 pseudovirus infects hepatic parenchymal cells mainly through an ASGR1-dependent mechanism.We confirmed that ASGR1 could interact with Spike protein,which depends on receptor binding domain(RBD)and N-terminal domain(NTD).Finally,we also used Immunohistochemistry and electron microscopy to verify that SARS-CoV-2 could infect primary hepatic parenchymal cells.After inhibiting ASGR1 in primary hepatic parenchymal cells by siRNA,the infection efficiency of the live virus decreased significantly.Collectively,these findings indicate that ASGR1 is a candidate receptor for SARS-CoV-2 that promotes infection of hepatic parenchymal cells.

Successful treatment of severe monkeypox case with advanced HIV infection using plasma from smallpoxvaccinated healthy population:A case report

Since the first reported case of monkeypox in the UK in May 2022,there has been an upward trend in monkeypox cases and a global outbreak.However,reports of severe cases are relatively limited.In this study,we report a case of severe monkeypox in a patient with HIV.The patient presented with skin lesions that started on his face and around the penis and persisted for several months.Throughout the course of the disease,he received systematic symp-tomatic supportive treatment,topical remedies,and special care for the rash.He also underwent cidofovir antiviral therapy and smallpox‐vaccinated healthy population‐derived plasma therapy in succession,with the condition ultimately showing improvement after plasma treatment.After more than 3 months of hospitalization,he fully recovered.To the best of our knowledge,this is the first reported use of smallpox‐vaccinated healthy population‐derived plasma in the treatment of severe monkeypox cases.

Association between the triglyceride to high-density lipoprotein cholesterol ratio and cardiovascular diseases in people living with human immunodeficiency virus:Evidence from a retrospectively cohort study 2005-2022

Introduction:The triglyceride to high-density lipoprotein cholesterol(TG/HDL-C)ratio,a novel biomarker for metabolic syndrome(MetS),has been validated in the general population as being significantly correlated with cardiovascular disease(CVD)risk.However,its capabilities to predict CVD in people living with human immunodeficiency virus(HIV;PLWH)remain underexplored.Methods:We conducted a retrospective cohort study of 16,081 PLWH who initiated antiretroviral therapy(ART)at the Third People’s Hospital of Shenzhen(China)from 2005 to 2022.The baseline TG/HDL-C ratio was calculated as TG(mmol/L)divided by HDL-C(mmol/L).We employed a multivariate Cox proportional hazards model to assess the association between the TG/HDL-C ratio and CVD occurrence,using Kaplan-Meier curves and log-rank tests to compare survival distributions.The increase in prediction risk upon the addition of the biomarker to the conventional risk model was examined through the assessment of changes in net reclassification improvement(NRI)and integrated discrimination improvement(IDI).Nonlinear relationships were investigated using a restricted cubic spline plot,complemented by a two-piecewise Cox proportional hazards model to analyze threshold effects.Results:At the median follow-up of 70 months,213 PLWH developed CVD.Kaplan-Meier curves demonstrated a significant association between the increased risk of CVD and a higher TG/HDL-C ratio(log-rank P<0.001).The multivariate-adjusted Cox proportional hazards regression model indicated that the CVD hazard ratios(HR)(95%confidence intervals[95%CIs])for Q2,Q3,and Q4 versus Q1 of the TG/HDL-C ratio were 2.07(1.24,3.45),2.17(1.32,3.57),and 2.20(1.35,3.58),respectively(P<0.05).The consideration of the TG/HDL-C ratio in the model,which included all significant factors for CVD incidence,improved the predictive risk,as indicated by the reclassification metrics(NRI 16.43%,95%CI 3.35%-29.52%,P=0.014).The restriction cubic spline plot demonstrated an upward trend between the TG/HDL-C ratio and the CVD occurrence(P for non-linear association=0.027,P for overall significance=0.009),with the threshold at 1.013.Significantly positive correlations between the TG/HDL-C ratio and CVD were observed below the TG/HDL-C ratio threshold with HR 5.88(95%CI 1.58-21.88,P=0.008),but not above the threshold with HR 1.01(95%CI 0.88-1.15,P=0.880).Conclusion:Our study confirms the effectiveness of the TG/HDL-C ratio as a predictor of CVD risk in PLWH,which demonstrates a significant nonlinear association.These findings indicate the potential of the TG/HDL-C ratio in facilitating early prevention and treatment strategies for CVD among PLWH.

Biomarkers for predicting efficacy of chimeric antigen receptor T cell therapy and their detection methods

Cancer immunotherapy has emerged as the fourth most prevalent approach to tumor treatment,alongside surgery,radiotherapy,and chemotherapy.After several decades of development,chimeric antigen receptor T(CAR-T)cell therapy,a promising branch of adoptive T-cell therapy,has demonstrated superior efficacy and safety in comparison to other cell therapies in the treatment of cancer.At present,CAR-T cells are predominantly used to treat hematological malignancies,although their application in solid tumors is being readily investigated.Although numerous studies have examined the biomarkers associated with the safety of CAR-T cell therapy,few have evaluated predictors of CAR-T cell therapeutic efficacy.Thus,the primary objective of this review article was to provide a comprehensive overview of the factors predicting the efficacy of CAR-T cell therapy,with a particular focus on biomarkers and their detection methods.

Diagnostic approaches for monkeypox virus

Mpox(formerly Monkeypox)is a zoonotic infection caused by Monkeypox virus(MPXV).Since 2022,Mpox epidemics have occurred in many nonendemic countries and regions,leading the World Health Organization to declare a public health emergency of international concern.With the persistent transmission and evolution of MPXV,symptoms of Mpox have become milder,with some infections being asymptomatic.In addition,MPXV has become more contagious.Therefore,rapid and accurate diagnosis and screening of MPXV is vital to prevent and control MPXV epidemics.Here,we review and summarize the technical details,application scenarios,and the advantages and disadvantages of MPXV‐specific diagnostic methods.

From bench to bedside:Opportunities and challenges for iLABMED

Since the new iLABMED was founded in June 2023,it has published three issues with 21 articles(till Dec 2023).As a journal majored in laboratory medicine,iLABMED also has to face many opportunities and challenges of laboratory medicine.This editorial summarized the main opportunities and challenges faced by iLABMED.The future prospects of laboratory medicine,which must be highlighted by iLABMED were also discussed based on a brief review of the current advances in laboratory medicine.iLABMED will continue to provide a useful platform for general‐interested,insightful,and informative articles with high quality.

Dysregulated STAT1 gain-of-function:Pathogen-free autoimmunity and fungal infection

Inborn errors of the signal transducer and activator of transcription 1(STAT1)result in four types of immunodeficiency disease with varying degrees of impaired STAT1 function:autosomal recessive(AR)complete STAT1 deficiency,AR partial STAT1 deficiency,autosomal dominant(AD)STAT1 deficiency,and AD STAT1 gain-of-function(STAT1-GOF).Of which,the STAT1-GOF mutations promote a clinical syndrome of immune dysregulation characterized by recurrent infections,especially chronic mucocutaneous candidiasis(CMC)and Talaromyces marneffei infection and predisposition to humoral autoimmunity.STAT1-GOF mutations lead to enhanced phosphorylation of STAT1(pSTAT1),delayed dephosphorylation,and impaired nuclear dephosphorylation.As a result,the development of T helper(Th)17 cells is impaired,limiting the production of interleukin(IL)-17,which plays an important role in antifungal immunity.Additionally,mutations can also cause a decrease in the proportion of CD4^(+),CD8^(+),and natural killer(NK)cells.Recent research demonstrated that in the absence of overt infection,STAT-GOF mice can disrupt naïve CD4^(+)T cell homeostasis and promote expansion and differentiation of abnormal T-follicular helper/T-helper 1-like(Tfh/Th1-like)T cells and germinal center-like(GC-like)B cells,and thus reminds us of the complex molecular mechanism of autoimmune disease with/without fungal infection,which may further involve specific clinical treatment including antifungal and anti-autoimmunity therapies.In addition,sex and location of mutation were also associated with the clinical phenotype.Individuals with DNA binding domain(DBD)mutations had a higher prevalence of autoimmunity and aberrant B cell activation.Disrupted CD4^(+)T cell homeostasis occurred sooner and more robustly in females,highlighting the importance of specific treatment to normalize STAT1 expression and restore immune tolerance in patients with STAT1-GOF syndrome.Herein,we provide a comprehensive review of STAT1-GOF aiming to further clarify the regulatory mechanism of cellular and humoral immune deficiency in patients with fungal infection with or without autoimmunity.

Durability of neutralizing antibodies and T-cell response post SARS-CoV-2 infection

The ongoing pandemic of coronavirus disease 19(COVID-19)is caused by a newly discoveredβcoronavirus named severe acute respiratory syndrome coronavirus 2(SARS-CoV-2).How long the adaptive immunity triggered by SARS-CoV-2 can last is of critical clinical relevance in assessing the probability of second infection and efficacy of vaccination.Here we examined,using ELISA,the IgG antibodies in serum specimens collected from 17 COVID-19 patients at 6–7 months after diagnosis and the results were compared to those from cases investigated 2 weeks to 2 months post-infection.All samples were positive for IgGs against the S-and N-proteins of SARS-CoV-2.Notably,14 samples available at 6–7 months post-infection all showed significant neutralizing activities in a pseudovirus assay,with no difference in blocking the cell-entry of the 614D and 614G variants of SARS-CoV-2.Furthermore,in 10 blood samples from cases at 6–7 months post-infection used for memory T-cell tests,we found that interferonγ-producing CD4+and CD8+cells were increased upon SARS-CoV-2 antigen stimulation.Together,these results indicate that durable anti-SARS-CoV-2 immunity is common in convalescent population,and vaccines developed from 614D variant may offer protection from the currently predominant 614D variant of SARS-CoV-2.

A SARS-CoV-2 antibody retains potent neutralization against Omicron by targeting conserved RBM residues

The newly emerged Omicron(B.1.1.529)variant of SARS-CoV-2 is quickly overtaking the Delta variant and becoming the dominant strain around the world due to its enhanced transmissibility and high immune escape potential[1,2].Compared to the Wuhan strain,the Omicron variant carries 37 spike mutations,of which 15 are within the receptor-binding domain(RBD)(Fig.1A).A high mutation rate is associated with remarkable resistance to current vaccines and RBD-specific antibody therapeutics[2,3,4].

Allogeneic gene-edited HIV-specific CAR-T cells secreting PD-1 blocking scFv enhance specific cytotoxic activity against HIV Envt cells in vivo

HIV-specific chimeric antigen receptor(CAR)T-cells have been developed to target HIV-1 infected CD4t T-cells that express HIV Env proteins.However,T cell exhaustion and the patient-specific autologous paradigm of CAR-T cell hurdled clinical applications.Here,we created HIV-specific CAR-T cells using human peripheral blood mononuclear cells and a 3BNC117-E27(3BE)CAR construct that enabled the expression of programmed cell death protein(PD-1)-blocking scFv E27 and the single-chain variable fragment of the HIV-1-specific broadly neutralizing antibody 3BNC117 to target native HIV Env.Compared with T cells expressing 3BNC117-CAR alone,3BE CAR-T cells showed greater cytotoxic activity against HIV Envt cells with stronger proliferation capability,higher killing efficiency,and enhanced cytokine secretion in the presence of HIV Env-expressing cells.Furthermore,we manufactured TCR-deficient 3BE CAR-T cells through gene editing and demonstrated that these CAR-T cells could effectively kill HIV Env^(+) cells in vivo without the occurrence of severe graft-versus-host disease(GvHD)in NSG mice.These data suggest that we have provided a feasible approach to the generation of“off-theshelf”anti-HIV CAR-T cells in combination with PD-1 checkpoint blockade immunotherapy,which can be a powerful therapeutic candidate for the functional cure of HIV.