Debate regarding the premature aging of knee joints in acquired immune deficiency syndrome(AIDS)patients has remained contentious,with conjectures pointing towards its correlation with distinct antiviral regimes.Prote...Debate regarding the premature aging of knee joints in acquired immune deficiency syndrome(AIDS)patients has remained contentious,with conjectures pointing towards its correlation with distinct antiviral regimes.Protease inhibitors(PIs)stand as a prominent class of antiviral agents frequently utilized in AIDS management and have been significantly linked to premature senescence.This study aimed to investigate whether PI-containing regimens would accelerate osteoarthritis(OA)development and explore the molecular mechanisms underlying this association.A retrospective cohort of 151 HIV-infected individuals,categorized into PI and non-PI groups,was established.Patients in PI group exhibited lower KOOS and a higher prevalence of radiological knee OA than those in non-PI group.Additionally,25 anti-HIV drugs were screened and among all antiviral drugs,lopinavir had the most detrimental impact on cartilage anabolism,accelerating cartilage senescence and promoting mouse OA development.Mechanistically,lopinavir accelerated cellular senescence by inhibiting Zmpste24 and interfering nuclear membrane stability,which leads to decreased binding between nuclear membrane-binding protein Usp7 and Mdm2 and activates Usp7/Mdm2/p53 pathway.Zmpste24 overexpression reduces OA severity in mice.These findings suggest that PI-containing regimens accelerate cartilage senescence and OA development through Zmpste24 inhibition,which provides new insights into the selection of HIV regimens.展开更多
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...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.展开更多
Background:Few data are available regarding the long-term case-fatality rate(CFR)among people living with HIV(PLWH)with nontuberculous mycobacteria(NTM)disease.The aim of this study is to analyze the long-term CFR in ...Background:Few data are available regarding the long-term case-fatality rate(CFR)among people living with HIV(PLWH)with nontuberculous mycobacteria(NTM)disease.The aim of this study is to analyze the long-term CFR in patients with NTM disease and to identify risk factors for their death.Methods:A retrospective cohort study of 379 cases of microbiologically confirmed NTM disease in PLWH was conducted from January 1,2012,to December 31,2020,in Shanghai,China.We used Kaplan-Meier survival analysis and the log-rank test to compare the long-term CFR in patients with disseminated NTM(DNTM)and localized NTM disease.Univariate Cox proportional hazards regression analysis and a stepwise Cox proportional hazards regression model were used to estimate the predictors of long-term CFR.Results:The cohort was followed up for a median of 26 months.The total CFR was 15.7%by one year and increased to 22.6%at 5 years after the diagnosis of NTM disease.The 5-year CFR of PLWH with DNTM was significantly higher than that of PLWH with localized NTM(26.7%vs 19.6%for DNTM and localized NTM disease,respectively).Older age[hazard ratio(HR)=1.04,95%confidence interval(CI):1.02-1.06,P<0.001],comorbidity(HR=2.05,95%CI:1.21-3.49,P<0.01),DNTM(HR=2.08,95%CI:1.17-3.68,P<0.05),and HIV viral load(HR=1.32,95%CI:1.12-1.55,P<0.001)were all independent risk factors for long-term CFR.In the subgroup analysis,time to culture positivity was negatively correlated with CFR in patients with DNTM(HR=0.90,95%CI:0.82-0.98,P<0.05).Conclusions:NTM was associated with a high long-term CFR in PLWH.Further approaches to prevent NTM disease in PLWH are urgently needed.展开更多
To the Editor:Coronavirus disease 2019(COVID-19),instigated by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),has manifested as a formidable global pandemic,precipitating significant economic implications...To the Editor:Coronavirus disease 2019(COVID-19),instigated by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),has manifested as a formidable global pandemic,precipitating significant economic implications and leading to extensive mortalities.Simultaneously,the acquired immune deficiency syndrome(AIDS)epidemic caused by the human immunodeficiency virus(HIV)persists as a salient global health exigency.Cumulatively by the termination of 2022,AIDS-related pathologies accounted for approximately 40.4 million fatalities,with an extant global HIV population of roughly 39 million people living with HIV(PLWH),as a potentially immunocompromised population,have received limited attention in the realm of COVID-19 research.展开更多
基金supported by Natural Science Foundation of China(82472476)Fundamental Research Funds for the Central Universities(YG2023ZD15)+2 种基金The Youth Talent Program from Shanghai Health System(2022YQ020)AI-Driven Reform of Research Paradigms Empowers Discipline Advancement Initiatives from Shanghai Municipal Education Commission(Grant No.JWAIZD-7)the Natural Science Foundation of Shanghai(23ZR1437300).
文摘Debate regarding the premature aging of knee joints in acquired immune deficiency syndrome(AIDS)patients has remained contentious,with conjectures pointing towards its correlation with distinct antiviral regimes.Protease inhibitors(PIs)stand as a prominent class of antiviral agents frequently utilized in AIDS management and have been significantly linked to premature senescence.This study aimed to investigate whether PI-containing regimens would accelerate osteoarthritis(OA)development and explore the molecular mechanisms underlying this association.A retrospective cohort of 151 HIV-infected individuals,categorized into PI and non-PI groups,was established.Patients in PI group exhibited lower KOOS and a higher prevalence of radiological knee OA than those in non-PI group.Additionally,25 anti-HIV drugs were screened and among all antiviral drugs,lopinavir had the most detrimental impact on cartilage anabolism,accelerating cartilage senescence and promoting mouse OA development.Mechanistically,lopinavir accelerated cellular senescence by inhibiting Zmpste24 and interfering nuclear membrane stability,which leads to decreased binding between nuclear membrane-binding protein Usp7 and Mdm2 and activates Usp7/Mdm2/p53 pathway.Zmpste24 overexpression reduces OA severity in mice.These findings suggest that PI-containing regimens accelerate cartilage senescence and OA development through Zmpste24 inhibition,which provides new insights into the selection of HIV regimens.
基金Ascletis Pharma Inc.and the Shanghai Commission of Science and Technology(grant no.20MC1920100,grant no.20Y31900400 and grant no.21Y11901200)。
文摘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.
基金Shanghai Commission of Science and Technology(20MC1920100 and 21Y11901200)Shanghai key Infectious Disease Project(shslczdzk01102)+2 种基金Shanghai Municipal Health Commission(GWV-10.1-XK02)development fund for Shanghai talents(2020089)Shanghai "Rising stars of Medical Talent" Youth Development Program(No. 2019-72)。
文摘Background:Few data are available regarding the long-term case-fatality rate(CFR)among people living with HIV(PLWH)with nontuberculous mycobacteria(NTM)disease.The aim of this study is to analyze the long-term CFR in patients with NTM disease and to identify risk factors for their death.Methods:A retrospective cohort study of 379 cases of microbiologically confirmed NTM disease in PLWH was conducted from January 1,2012,to December 31,2020,in Shanghai,China.We used Kaplan-Meier survival analysis and the log-rank test to compare the long-term CFR in patients with disseminated NTM(DNTM)and localized NTM disease.Univariate Cox proportional hazards regression analysis and a stepwise Cox proportional hazards regression model were used to estimate the predictors of long-term CFR.Results:The cohort was followed up for a median of 26 months.The total CFR was 15.7%by one year and increased to 22.6%at 5 years after the diagnosis of NTM disease.The 5-year CFR of PLWH with DNTM was significantly higher than that of PLWH with localized NTM(26.7%vs 19.6%for DNTM and localized NTM disease,respectively).Older age[hazard ratio(HR)=1.04,95%confidence interval(CI):1.02-1.06,P<0.001],comorbidity(HR=2.05,95%CI:1.21-3.49,P<0.01),DNTM(HR=2.08,95%CI:1.17-3.68,P<0.05),and HIV viral load(HR=1.32,95%CI:1.12-1.55,P<0.001)were all independent risk factors for long-term CFR.In the subgroup analysis,time to culture positivity was negatively correlated with CFR in patients with DNTM(HR=0.90,95%CI:0.82-0.98,P<0.05).Conclusions:NTM was associated with a high long-term CFR in PLWH.Further approaches to prevent NTM disease in PLWH are urgently needed.
文摘To the Editor:Coronavirus disease 2019(COVID-19),instigated by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),has manifested as a formidable global pandemic,precipitating significant economic implications and leading to extensive mortalities.Simultaneously,the acquired immune deficiency syndrome(AIDS)epidemic caused by the human immunodeficiency virus(HIV)persists as a salient global health exigency.Cumulatively by the termination of 2022,AIDS-related pathologies accounted for approximately 40.4 million fatalities,with an extant global HIV population of roughly 39 million people living with HIV(PLWH),as a potentially immunocompromised population,have received limited attention in the realm of COVID-19 research.
