INTRODUCTIONIt has now been almost 20 years since the initialdescriptions of a heretofore unrecognized disorderafflicting homosexual men and manifesting asPneumocystis carinii pneumonia and Kaposi’ssarcoma.With the i...INTRODUCTIONIt has now been almost 20 years since the initialdescriptions of a heretofore unrecognized disorderafflicting homosexual men and manifesting asPneumocystis carinii pneumonia and Kaposi’ssarcoma.With the identification of the humanimmunodeficiency virus(HIV) as the etiology ofthis syndrome,there has been exponential growth inour understanding of this devastating展开更多
Natural killer (NK) cell plays an important role in an innate immune response against viral infection. The kinetics regulation and functional consequences of NK cells in the pathogeneses of diseases are uncertain. We ...Natural killer (NK) cell plays an important role in an innate immune response against viral infection. The kinetics regulation and functional consequences of NK cells in the pathogeneses of diseases are uncertain. We analyzed NK cell distribution and function of successfully combination antiretroviral therapy (cART)-treated HIV-1 infected individuals in Khon Kaen Regional Hospital, Thailand. The results demonstrated that increased percentage and the total number of NK cell in cART-treated HIV-1 infected patients with preferential high levels of CD56dimCD16+ and CD56-CD16+ subsets when compared with a control group even in undetectable viral load (<40 copies per milliliter). Concomitantly, decreased cytotoxic activity measured by CD107asurface expression with maintained IFN-γ production implied the impairment of cytolytic activity was not recovered after cART treatment. Thus, altered NK cell frequency and function by HIV-1 infection are not completely recovered with cART, which may contribute to impaired cellular immune response and persistence of HIV-1.展开更多
AIM: To assess whether reasons for hepatitis C virus(HCV) therapy non-initiation differentially affect racial and ethnic minorities with human immunodeficiency virus(HIV)/HCV co-infection.METHODS: Analysis included co...AIM: To assess whether reasons for hepatitis C virus(HCV) therapy non-initiation differentially affect racial and ethnic minorities with human immunodeficiency virus(HIV)/HCV co-infection.METHODS: Analysis included co-infected HCV treatment-na?ve patients in the University of North Carolina CFAR HIV Clinical Cohort(January 1, 2004 and December31, 2011). Medical records were abstracted to document non-modifiable medical(e.g., hepatic decompensation, advanced immunosuppression), potentially modifiable medical(e.g., substance abuse, severe depression, psychiatric illness), and non-medical(e.g., personal,social, and economic factors) reasons for non-initiation. Statistical differences in the prevalence of reasons for non-treatment between racial/ethnic groups were assessed using the two-tailed Fisher's exact test. Three separate regression models were fit for each reason category. Odds ratios and their 95%CIs(Wald's) were computed.RESULTS: One hundred and seventy-one patients with HIV/HCV co-infection within the cohort met study inclusion. The study sample was racially and ethnically diverse; most patients were African-American(74%), followed by Caucasian(19%), and Hispanic/other(7%). The median age was 46 years(interquartile range = 39-50) and most patients were male(74%). Among the 171 patients, reasons for non-treatment were common among all patients, regardless of race/ethnicity(50% with ≥ 1 non-modifiable medical reason, 66% with ≥1 potentially modifiable medical reason, and 66% with ≥ 1 non-medical reason). There were no significant differences by race/ethnicity. Compared to Caucasians, African-Americans did not have increased odds of nonmodifiable [adjusted odds ratio(a OR) = 1.47, 95%CI: 0.57-3.80], potentially modifiable(a OR = 0.72, 95%CI: 0.25-2.09) or non-medical(a OR = 0.90, 95%CI: 0.32-2.52) reasons for non-initiation.CONCLUSION: Race/ethnicity alone is not predictive of reasons for HCV therapy non-initiation. Targeted interventions are needed to improve access to therapy for all co-infected patients, including minorities.展开更多
Background:Over 90%of Human Immunodeficiency Virus(HIV)infected individuals will be on treatment by 2020under UNAIDS 90-90-90 global targets.Under World Health Organisation(WHO)"Treat All"approach,this numbe...Background:Over 90%of Human Immunodeficiency Virus(HIV)infected individuals will be on treatment by 2020under UNAIDS 90-90-90 global targets.Under World Health Organisation(WHO)"Treat All"approach,this number will be approximately 36.4 million people with over 98%in low-income countries(LICs).Main body:Pretreatment drug resistance(PDR)largely driven by frequently use of non-nucleoside reverse transcriptase inhibitors(NNRTIs),efavirenz and nevirapine,has been increasing with roll-out of combined antiretroviral therapy(cART)with 29%annual increase in some LICs countries.PDR has exceeded 10%in most LICs which warrants change of first line regimen to more robust classes under WHO recommendations.If no change in regimens is enforced in LICs,it’s estimated that over 16%of total deaths,9%of new infections,and 8%of total cART costs will be contributed by HIV drug resistance by 2030.Less than optimal adherence,and adverse side effects associated with currently available drug regimens,all pose a great threat to achievement of 90%viral suppression and elimination of AIDS as a public health threat by 2030.This calls for urgent introduction of policies that advocate for voluntary and compulsory drug licensing of new more potent drugs which should also emphasize universal access of these drugs to all individuals worldwide.Conclusions:The achievement of United Nations Programme on HIV and AIDS 2020 and 2030 targets in LICs depends on access to active cART with higher genetic barrier to drug resistance,better safety,and tolerability profiles.It’s also imperative to strengthen quality service delivery in terms of retention of patients to treatment,support for adherence to cART,patient follow up and adequate drug stocks to help achieve a free AIDS generation.展开更多
Viral protein U （Vpu） is an accessory protein associated with two main functions important in human immu-nodeficiency virus type 1 （HIV-1） replication and dis-semination; these are down-regulation of CD4 receptor ...Viral protein U （Vpu） is an accessory protein associated with two main functions important in human immu-nodeficiency virus type 1 （HIV-1） replication and dis-semination; these are down-regulation of CD4 receptor through mediating its proteasomal degradation and en-hancement of virion release by antagonizing tetherin/BST2. It is also well established that Vpu is one of the most highly variable proteins in the HIV-1 proteome. However it is still unclear what drives Vpu sequence variability, whether Vpu acquires polymorphisms as a means of immune escape, functional advantage, or otherwise. It is assumed that the host-pathogen inter-action is a cause of polymorphic phenotype of Vpu and that the resulting functional heterogeneity of Vpu may have critical significance in vivo . In order to compre-hensively understand Vpu variability, it is important to integrate at the population level the genetic association approaches to identify specifc amino acid residues and the immune escape kinetics which may impose Vpu functional constraints in vivo . This review will focus on HIV-1 accessory protein Vpu in the context of its sequence variability at population level and also bring forward evidence on the role of the host immune re-sponses in driving Vpu sequence variability; we will also highlight the recent findings that illustrate Vpu func-tional implication in HIV-1 pathogenesis.展开更多
Objective: It is in order to estimate the prevalence and incidence of HIV, the frequency of sexual risk behaviors, and perceptions of available resources to prevent and treat HIV among crack users in the San Salvador ...Objective: It is in order to estimate the prevalence and incidence of HIV, the frequency of sexual risk behaviors, and perceptions of available resources to prevent and treat HIV among crack users in the San Salvador Metropolitan Area. Methods: We conducted a survey of 420 crack users by using respondent-driven sampling to measure demographic characteristics, the quantity and frequency of drug use, history of STIs, including HIV, and experiences with organizations which provide prevention and treatment of HIV. Each participant offered a free and voluntary HIV test and was asked permission to share the results of the test with the study. Bernoullian modeling was used to estimate the prevalence and incidence of HIV among heterosexual males in this population. Results: The estimated prevalence was 7% (95% CI: 2.3% -9.8%) among participants who agreed to take the test and share the results, and 4.9% (95% CI: 2.8% -7.8%) assuming that those who did not take the test or share results were seronegative. Participants reported a high frequency of sexual risk behaviors. In addition, participants were reported to have little knowledge of organizations to prevent or treat HIV/AIDS;58% had never taken an HIV test prior to survey administration. Conclusions: Crack users in San Salvador are at high risk for HIV acquisition. HIV prevention interventions are urgently needed, especially interventions increasing access to HIV testing and prevention.展开更多
The cure or functional cure of the"Berlin patient"and"London patient"indicates that infusion of HIV-resistant cells could be a viable treatment strategy.Very recently,we genetically linked a short-...The cure or functional cure of the"Berlin patient"and"London patient"indicates that infusion of HIV-resistant cells could be a viable treatment strategy.Very recently,we genetically linked a short-peptide fusion inhibitor with a glycosylphosphatidylinositol(GPI)attachment signal,rendering modified cells fully resistant to HIV infection.In this study,GPI-anchored m36.4,a single-domain antibody(nanobody)targeting the coreceptor-binding site of gp120,was constructed with a lentiviral vector.We verified that m36.4 was efficiently expressed on the plasma membrane of transduced TZM-bl cells and targeted lipid raft sites without affecting the expression of HIV receptors(CD4,CCR5,and CXCR4).Significantly,TZM-bl cells expressing GPI-m36.4 were highly resistant to infection with divergent HIV-1 subtypes and potently blocked HIV-1 envelope-mediated cell-cell fusion and cell-cell viral transmission.Furthermore,we showed that GPI-m36.4-modified human CEMss-CCR5 cells were nonpermissive to both CCR5-and CXCR4-tropic HIV-1 isolates and displayed a strong survival advantage over unmodified cells.It was found that GPI-m36.4 could also Impair HIV-1 Env processing and viral infectivity in transduced cells,underlying a multifaceted mechanism of antiviral action.In conclusion,our studies characterize m36.4 as a powerful nanobody that can generate HIV-resistant cells,offering a novel gene therapy approach that can be used alone or in combination.展开更多
Very recently,the Dusseldorf University Hospital in Germany reported the third patient who was cured of HIV after CCR5△32 hematopoietic stem cell transplantation(HSCT)[1].There is increasing evidence that a cure can ...Very recently,the Dusseldorf University Hospital in Germany reported the third patient who was cured of HIV after CCR5△32 hematopoietic stem cell transplantation(HSCT)[1].There is increasing evidence that a cure can be achieved through infusion of HIV-resistant cells for gene therapy.Toward this goal,we focus on cell membrane anchoring strategies by glycosylphosphatidylinositol(GPl),as illustrated in Fig.1.For example,genetically anchoring the single-domain antibody m36.4(nanobody)that targets the coreceptor-binding site of gp120 through the GPl attachment signal might render modified cells fully resistant to HIV infection,block HIV-1 envelope-mediated cell-cell fusion and cell-cell viral transmission,and interfere with viral genesis[2].展开更多
Innate immunity represents one of the main host responses to viral infection.1,2,3 STING(Stimulator of interferon genes),a crucial immune adapter functioning in host cells,mediates cGAS(Cyclic GMP-AMP Synthase)sensing...Innate immunity represents one of the main host responses to viral infection.1,2,3 STING(Stimulator of interferon genes),a crucial immune adapter functioning in host cells,mediates cGAS(Cyclic GMP-AMP Synthase)sensing of exogenous and endogenous DNA fragments and generates innate immune responses.4 Whether STING activation was involved in infection and replication of enterovirus remains largely unknown.In the present study,we discovered that human enterovirus A71(EV-A71)infection triggered STING activation in a cGAS dependent manner.EV-A71 infection caused mitochondrial damage and the discharge of mitochondrial DNA into the cytosol of infected cells.However,during EV-A71 infection,cGAS-STING activation was attenuated.EV-A71 ^(pro)teins were screened and the viral ^(pro)tease 2A^(pro) had the greatest capacity to inhibit cGAS-STING activation.We identified TRAF3 as an important factor during STING activation and as a target of 2A^(pro).Supplement of TRAF3 rescued cGAS-STING activation suppression by 2A^(pro).TRAF3 supported STING activation mediated TBK1 phosphorylation.Moreover,we found that 2A^(pro) ^(pro)tease activity was essential for inhibiting STING activation.Furthermore,EV-D68 and CV-A16 infection also triggered STING activation.The viral ^(pro)tease 2A^(pro) from EV-D68 and CV-A16 also had the ability to inhibit STING activation.As STING activation prior to EV-A71 infection generated cellular resistance to EV-A71 replication,blocking EV-A71-mediated STING suppression represents a new anti-viral target.展开更多
The advent of tyrosine kinase inhibitor(TKI)therapy markedly improved the outcome of patients with chronic-phase chronic myeloid leukemia(CML).However,the poor prognosis of patients with advanced-phase CML and the lif...The advent of tyrosine kinase inhibitor(TKI)therapy markedly improved the outcome of patients with chronic-phase chronic myeloid leukemia(CML).However,the poor prognosis of patients with advanced-phase CML and the lifelong dependency on TKIs are remaining challenges;therefore,an effective therapeutic has been sought.The BCR–ABL p210 fusion protein’s junction region represents a leukemia-specific neoantigen and is thus an attractive target for antigen-specific T-cell immunotherapy.BCR–ABL p210 fusion-region-specific CD4+T-helper(Th)cells possess antileukemic potential,but their function remains unclear.In this study,we established a BCR–ABL p210 b3a2 fusion-region-specific CD4+Th-cell clone(b3a2-specific Th clone)and examined its dendritic cell(DC)-mediated antileukemic potential.The b3a2-specific Th clone recognized the b3a2 peptide in the context of HLA-DRB1*09:01 and exhibited a Th1 profile.Activation of this clone through T-cell antigen receptor stimulation triggered DC maturation,as indicated by upregulated production of CD86 and IL-12p70 by DCs,which depended on CD40 ligation by CD40L expressed on b3a2-specific Th cells.Moreover,in the presence of HLA-A*24:02-restricted Wilms tumor 1(WT1)235–243 peptide,DCs conditioned by b3a2-specific Th cells efficiently stimulated the primary expansion of WTI-specific cytotoxic T lymphocytes(CTLs).The expanded CTLs were cytotoxic toward WT1235–243-peptide-loaded HLA-A*24:02-positive cell lines and exerted a potent antileukemic effect in vivo.However,the b3a2-specific Th-clone-mediated antileukemic CTL responses were strongly inhibited by both TKIs and interferon-α.Our findings indicate a crucial role of b3a2-specific Th cells in leukemia antigen-specific CTL-mediated immunity and provide an experimental basis for establishing novel CML immunotherapies.展开更多
Objective:To investigate the impacts of two herbal preparations for human immunodeficiency virus/aquired immune deficiency syndrome(HIV/AIDS)patients,Shenling Fuzheng Capsule(参灵扶正胶囊,SLFZC)and Qingdu Capsule(清...Objective:To investigate the impacts of two herbal preparations for human immunodeficiency virus/aquired immune deficiency syndrome(HIV/AIDS)patients,Shenling Fuzheng Capsule(参灵扶正胶囊,SLFZC)and Qingdu Capsule(清毒胶囊,QDC),on the efficacy of highly active antiretroviral therapy(HAART).Methods:HIV/AIDS patients met the criteria were all enrolled in a 1-year cohort study,in which patients receiving HAART alone were designated as Group A,those receiving HAART in combination with SLFZC were designated as Group B,and those receiving HAART in combination with QDC were designated as Group C,100 cases in each group.The dose of SLFZC was 1.48 g(4 capsules),3 times daily,and QDC 1.56 g(4 capsules),3 times daily.T cell subsets,HIV RNA and HIV-1 drug resistance were detected at enrollment and 1 year after treatment.Patients were followed up every 3 months,during which side-effects and other clinical data were recorded.Results:After 1-year treatment,the median increment in CD4 counts was 165.0,178.0 and 145.0 cells/μL for Group A,B and C,respectively.HIV RNA was undetectable in 94%of patients in Group A,96%in Group B and 92%in Group C.There were no differences regarding the increment in CD4 counts,HIV RNA and frequency of HIV-1 drug resistance mutations.Two of the 14 suspected side-effect symptoms,i.e.fatigue and dizziness,were lower in Groups B and C than in Group A(P<0.05,respectively).Conclusion:SLFZC and QDC do not have a negative impact on immunological and virological response to HAART;however,these preparations are not as potent in reducing HAART-associated side-effects as anticipated.展开更多
Background:Thymidine analogs,namely AZT(Zidovudine or Retrovir^(TM))and d4T(Stavudine or Zerit^(TM))are antiretroviral drugs still employed in over 75%of first line combination antiretroviral therapy(cART)in Kampala,U...Background:Thymidine analogs,namely AZT(Zidovudine or Retrovir^(TM))and d4T(Stavudine or Zerit^(TM))are antiretroviral drugs still employed in over 75%of first line combination antiretroviral therapy(cART)in Kampala,Uganda despite aversion to prescribing these drugs for cART in high income countries due in part to adverse events.For this study,we explored how the continued use of these thymidine analogs in cART could impact emergence of drug resistance and impact on future treatment success in Uganda,a low-income country.Methods:We examined the drug resistance genotypes by Sanger sequencing of 262 HIV-infected patients failing a first line combined antiretroviral treatment containing either AZT or d4T,which represents approximately 5%of the patients at the Joint Clinical Research Center receiving a AZT or d4T containing treatment.Next generation sequencing(DEEPGEN^(TM)HIV)and multiplex oligonucleotide ligation assays(AfriPOLA)were then performed on a subset of patient samples to detect low frequency drug resistant mutations.CD4 cell counts,viral RNA loads,and treatment changes were analyzed in a cohort of treatment success and failures.Results:Over 80%of patients failing first line AZT/d4T-containing cART had predicted drug resistance to 3TC(Lamivudine)and non-nucleoside RT inhibitors(NNRTIs)in the treatment regimen but only 45%had resistance AZT/d4T associated resistance mutations(TAMs).TAMs were however detected at low frequency within the patients HIV quasispecies(1-20%)in 21 of 34 individuals who were failing first-line AZT-containing cART and lacked TAMs by Sanger.Due to lack of TAMs by Sanger,AZT was typically maintained in second-line therapies and these patients had a low frequency of subsequent virologic success.Conclusions:Our findings suggest that continued use of AZT and d4T in first-line treatment in low-to-middle income countries may lead to misdiagnosis of HIV-1 drug resistance and possibly enhance a succession of second-and third-line treatment failures.展开更多
Untreated human immunodeficiency virus(HIV)infections usually lead to death from AIDS,although the rate of the disease progression varies widely among individuals.The cytotoxic T lymphocyte(CTL)response,which is restr...Untreated human immunodeficiency virus(HIV)infections usually lead to death from AIDS,although the rate of the disease progression varies widely among individuals.The cytotoxic T lymphocyte(CTL)response,which is restricted by highly polymorphic MHC class I alleles,plays a central role in controlling HIV replication.It is now recognized that the antiviral efficacy of CTLs at the single cell level is dependent on their antigen specificity and is important in determining the quality of host response to viruses so that the individual will remain asymptomatic.However,because of the extreme mutational plasticity of HIV,HIV-specific CTL responses are continuously and dynamically changing.In order to rationally design an effective vaccine,the questions as to what constitutes an effective antiviral CTL response and what characterizes a potent antigenic peptide to induce such responses are becoming highlighted as needing to be answered.展开更多
Monkeypox(mpox)outbreak in 2022 has caused more than 91,000 cases,has spread to 115 countries,regions,and territories,and has thus attracted much attention.The stability of poxvirus particles in the environment is rec...Monkeypox(mpox)outbreak in 2022 has caused more than 91,000 cases,has spread to 115 countries,regions,and territories,and has thus attracted much attention.The stability of poxvirus particles in the environment is recognized as an important factor in determining their transmission.However,few studies have investigated the persistence of poxviruses on material surfaces under various environmental conditions,and their sensitivity to biocides.Here,we systematically measured the stability of vaccinia virus(VACV)under different environmental conditions and sensitivity to inactivation methods via plaque assay,quantitative real‐time polymerase chain reaction(qPCR),and Gaussia luciferase(G‐luciferase)reporter system.The results show that VACV is stable on the surface of stainless steel,glass,clothing,plastic,towel,A4 paper,and tissue and persists much longer at 4℃ and?20℃,but is effectively inactivated by ultraviolet(UV)irradiation,heat treatment,and chemical reagents.Our study raises the awareness of long persistence of poxviruses in the environment and provides a simple solution to inactivate poxviruses using common disinfectants,which is expected to help the control and prevention of mpox virus and future poxvirus outbreaks.展开更多
Background andAims:Hepatitis C Virus(HCV)is uniformly recurrent after liver transplant(LT)and recurrence is associated with an increased risk of mortality.Immunosuppressive medications increase the risk of chronic kid...Background andAims:Hepatitis C Virus(HCV)is uniformly recurrent after liver transplant(LT)and recurrence is associated with an increased risk of mortality.Immunosuppressive medications increase the risk of chronic kidney disease,and the presence of chronic kidney disease presents a challenge for HCV treatment in LT recipients.The aim of this study was to assess changes in glomerular filtration rates(GFRs)of LT recipients receiving HCV treatment.Methods:This is a retrospective study of LT patients who received HCV treatment between 2015 and 2016(n=60).The outcomes of interest were differences in serum creatinine levels and in GFR,measured at treatment initiation and at 24 weeks after treatment.The average age of the patients was 59 years-old,and 17%were cirrhotic and 67%were treatment-experienced.All patients received sofosbuvir/ledipasvir without ribavirin.Results:All patients achieved sustained virologic response at 12 weeks after treatment(SVR12).At baseline,55%of patients had GFR<60 mL/min per 1.73 m2.Among those patients,GFR did not change in 18%,33%had improved GFR,and 48%had worsened GFR.Up to 45%of the patients had a GFR>60 mL/min per 1.73 m2.Among those patients,GFR did not change in 81%,and 19%had worsened GFR.In the entire cohort,65%of patients had improved or stable GFR and 35%had worsened GFR.The average change in serum creatinine between baseline and 24 weeks was 0.10(p=0.18).Conclusions:This study showed improved or unchanged GFR in 65%and worsened GFR in 35%of LT recipients who achieved SVR12.Worsening of GFR was more frequently encountered in those with impaired renal function at baseline.Caution should be used when treating HCV in LT recipients,especially those with baseline status of renal impairment.展开更多
COVID-19 is another major pandemic of viral infectious disease in the 21st century. Since the first case was reported in Wuhan, China, in December 2019, COVID-19 has resulted in more than 100 million confirmed cases a...COVID-19 is another major pandemic of viral infectious disease in the 21st century. Since the first case was reported in Wuhan, China, in December 2019, COVID-19 has resulted in more than 100 million confirmed cases and more than 2 million deaths. COVID-19 has been considered to be a systemic inflammatory response syndrome caused by SARS-CoV-2 infection, mainly with pulmonary lesions. Most patients have mild symptoms and a good prognosis, but severe or critical cases can lead to death. Otherwise, there is no effective antiviral drug to treat COVID-19.展开更多
文摘INTRODUCTIONIt has now been almost 20 years since the initialdescriptions of a heretofore unrecognized disorderafflicting homosexual men and manifesting asPneumocystis carinii pneumonia and Kaposi’ssarcoma.With the identification of the humanimmunodeficiency virus(HIV) as the etiology ofthis syndrome,there has been exponential growth inour understanding of this devastating
文摘Natural killer (NK) cell plays an important role in an innate immune response against viral infection. The kinetics regulation and functional consequences of NK cells in the pathogeneses of diseases are uncertain. We analyzed NK cell distribution and function of successfully combination antiretroviral therapy (cART)-treated HIV-1 infected individuals in Khon Kaen Regional Hospital, Thailand. The results demonstrated that increased percentage and the total number of NK cell in cART-treated HIV-1 infected patients with preferential high levels of CD56dimCD16+ and CD56-CD16+ subsets when compared with a control group even in undetectable viral load (<40 copies per milliliter). Concomitantly, decreased cytotoxic activity measured by CD107asurface expression with maintained IFN-γ production implied the impairment of cytolytic activity was not recovered after cART treatment. Thus, altered NK cell frequency and function by HIV-1 infection are not completely recovered with cART, which may contribute to impaired cellular immune response and persistence of HIV-1.
基金Supported by The University of North Carolina at Chapel Hill Center for AIDS Research(CFAR)an NIH funded program to Dr.Oramasionwu,No.P30 AI50410supported partially by the NIH Loan Repayment Program(LRP)through the National Institute on Minority Health and Health Disparities,No.L60 MD003770
文摘AIM: To assess whether reasons for hepatitis C virus(HCV) therapy non-initiation differentially affect racial and ethnic minorities with human immunodeficiency virus(HIV)/HCV co-infection.METHODS: Analysis included co-infected HCV treatment-na?ve patients in the University of North Carolina CFAR HIV Clinical Cohort(January 1, 2004 and December31, 2011). Medical records were abstracted to document non-modifiable medical(e.g., hepatic decompensation, advanced immunosuppression), potentially modifiable medical(e.g., substance abuse, severe depression, psychiatric illness), and non-medical(e.g., personal,social, and economic factors) reasons for non-initiation. Statistical differences in the prevalence of reasons for non-treatment between racial/ethnic groups were assessed using the two-tailed Fisher's exact test. Three separate regression models were fit for each reason category. Odds ratios and their 95%CIs(Wald's) were computed.RESULTS: One hundred and seventy-one patients with HIV/HCV co-infection within the cohort met study inclusion. The study sample was racially and ethnically diverse; most patients were African-American(74%), followed by Caucasian(19%), and Hispanic/other(7%). The median age was 46 years(interquartile range = 39-50) and most patients were male(74%). Among the 171 patients, reasons for non-treatment were common among all patients, regardless of race/ethnicity(50% with ≥ 1 non-modifiable medical reason, 66% with ≥1 potentially modifiable medical reason, and 66% with ≥ 1 non-medical reason). There were no significant differences by race/ethnicity. Compared to Caucasians, African-Americans did not have increased odds of nonmodifiable [adjusted odds ratio(a OR) = 1.47, 95%CI: 0.57-3.80], potentially modifiable(a OR = 0.72, 95%CI: 0.25-2.09) or non-medical(a OR = 0.90, 95%CI: 0.32-2.52) reasons for non-initiation.CONCLUSION: Race/ethnicity alone is not predictive of reasons for HCV therapy non-initiation. Targeted interventions are needed to improve access to therapy for all co-infected patients, including minorities.
文摘Background:Over 90%of Human Immunodeficiency Virus(HIV)infected individuals will be on treatment by 2020under UNAIDS 90-90-90 global targets.Under World Health Organisation(WHO)"Treat All"approach,this number will be approximately 36.4 million people with over 98%in low-income countries(LICs).Main body:Pretreatment drug resistance(PDR)largely driven by frequently use of non-nucleoside reverse transcriptase inhibitors(NNRTIs),efavirenz and nevirapine,has been increasing with roll-out of combined antiretroviral therapy(cART)with 29%annual increase in some LICs countries.PDR has exceeded 10%in most LICs which warrants change of first line regimen to more robust classes under WHO recommendations.If no change in regimens is enforced in LICs,it’s estimated that over 16%of total deaths,9%of new infections,and 8%of total cART costs will be contributed by HIV drug resistance by 2030.Less than optimal adherence,and adverse side effects associated with currently available drug regimens,all pose a great threat to achievement of 90%viral suppression and elimination of AIDS as a public health threat by 2030.This calls for urgent introduction of policies that advocate for voluntary and compulsory drug licensing of new more potent drugs which should also emphasize universal access of these drugs to all individuals worldwide.Conclusions:The achievement of United Nations Programme on HIV and AIDS 2020 and 2030 targets in LICs depends on access to active cART with higher genetic barrier to drug resistance,better safety,and tolerability profiles.It’s also imperative to strengthen quality service delivery in terms of retention of patients to treatment,support for adherence to cART,patient follow up and adequate drug stocks to help achieve a free AIDS generation.
基金Supported by A Grant-in-Aid for Scientific Research from the Ministry of Education,Science,Sports,and Culture(MEXT)of JapanA Grant-in-Aid for AIDS Research from the Ministry of Health,Labor,and Welfare of Japan+1 种基金The Scholarship for the International Priority Graduate Programs,to Hasan Z and Kamori DAdvanced Graduate Courses for International Students(Doctoral Course),MEXT,Japan,to Hasan Z and Kamori D
文摘Viral protein U （Vpu） is an accessory protein associated with two main functions important in human immu-nodeficiency virus type 1 （HIV-1） replication and dis-semination; these are down-regulation of CD4 receptor through mediating its proteasomal degradation and en-hancement of virion release by antagonizing tetherin/BST2. It is also well established that Vpu is one of the most highly variable proteins in the HIV-1 proteome. However it is still unclear what drives Vpu sequence variability, whether Vpu acquires polymorphisms as a means of immune escape, functional advantage, or otherwise. It is assumed that the host-pathogen inter-action is a cause of polymorphic phenotype of Vpu and that the resulting functional heterogeneity of Vpu may have critical significance in vivo . In order to compre-hensively understand Vpu variability, it is important to integrate at the population level the genetic association approaches to identify specifc amino acid residues and the immune escape kinetics which may impose Vpu functional constraints in vivo . This review will focus on HIV-1 accessory protein Vpu in the context of its sequence variability at population level and also bring forward evidence on the role of the host immune re-sponses in driving Vpu sequence variability; we will also highlight the recent findings that illustrate Vpu func-tional implication in HIV-1 pathogenesis.
文摘Objective: It is in order to estimate the prevalence and incidence of HIV, the frequency of sexual risk behaviors, and perceptions of available resources to prevent and treat HIV among crack users in the San Salvador Metropolitan Area. Methods: We conducted a survey of 420 crack users by using respondent-driven sampling to measure demographic characteristics, the quantity and frequency of drug use, history of STIs, including HIV, and experiences with organizations which provide prevention and treatment of HIV. Each participant offered a free and voluntary HIV test and was asked permission to share the results of the test with the study. Bernoullian modeling was used to estimate the prevalence and incidence of HIV among heterosexual males in this population. Results: The estimated prevalence was 7% (95% CI: 2.3% -9.8%) among participants who agreed to take the test and share the results, and 4.9% (95% CI: 2.8% -7.8%) assuming that those who did not take the test or share results were seronegative. Participants reported a high frequency of sexual risk behaviors. In addition, participants were reported to have little knowledge of organizations to prevent or treat HIV/AIDS;58% had never taken an HIV test prior to survey administration. Conclusions: Crack users in San Salvador are at high risk for HIV acquisition. HIV prevention interventions are urgently needed, especially interventions increasing access to HIV testing and prevention.
基金supported by grants from the CAMS Innovation Fund for Medical Sciences(2017-I2M-1-014)National Science and Technology Major Project of China(2018ZX10301103 and 2017ZX10202102-001-003)National Natural Science Foundation of China(81630061).
文摘The cure or functional cure of the"Berlin patient"and"London patient"indicates that infusion of HIV-resistant cells could be a viable treatment strategy.Very recently,we genetically linked a short-peptide fusion inhibitor with a glycosylphosphatidylinositol(GPI)attachment signal,rendering modified cells fully resistant to HIV infection.In this study,GPI-anchored m36.4,a single-domain antibody(nanobody)targeting the coreceptor-binding site of gp120,was constructed with a lentiviral vector.We verified that m36.4 was efficiently expressed on the plasma membrane of transduced TZM-bl cells and targeted lipid raft sites without affecting the expression of HIV receptors(CD4,CCR5,and CXCR4).Significantly,TZM-bl cells expressing GPI-m36.4 were highly resistant to infection with divergent HIV-1 subtypes and potently blocked HIV-1 envelope-mediated cell-cell fusion and cell-cell viral transmission.Furthermore,we showed that GPI-m36.4-modified human CEMss-CCR5 cells were nonpermissive to both CCR5-and CXCR4-tropic HIV-1 isolates and displayed a strong survival advantage over unmodified cells.It was found that GPI-m36.4 could also Impair HIV-1 Env processing and viral infectivity in transduced cells,underlying a multifaceted mechanism of antiviral action.In conclusion,our studies characterize m36.4 as a powerful nanobody that can generate HIV-resistant cells,offering a novel gene therapy approach that can be used alone or in combination.
基金supported in part by research grants from the National Natural Science Foundation of China(No.82230076)the CAMS Innovation Fund for Medical Sciences(2021-2M-1-037).
文摘Very recently,the Dusseldorf University Hospital in Germany reported the third patient who was cured of HIV after CCR5△32 hematopoietic stem cell transplantation(HSCT)[1].There is increasing evidence that a cure can be achieved through infusion of HIV-resistant cells for gene therapy.Toward this goal,we focus on cell membrane anchoring strategies by glycosylphosphatidylinositol(GPl),as illustrated in Fig.1.For example,genetically anchoring the single-domain antibody m36.4(nanobody)that targets the coreceptor-binding site of gp120 through the GPl attachment signal might render modified cells fully resistant to HIV infection,block HIV-1 envelope-mediated cell-cell fusion and cell-cell viral transmission,and interfere with viral genesis[2].
基金This work was supported,in part,by following fundings:the National Natural Science Foundation of China(number 31970151,92169203,81701988,31900133,82172239,82102384,32041006,81772169)the National Natural Science Foundation of Zhejiang Province(LQ21C010001 and LY22C080002,)the Leading innovative and Entrepreneur Team Introduction Program of Zhejiang(2019R01007).We thank Yifei Shi kindly provided key reagents.
文摘Innate immunity represents one of the main host responses to viral infection.1,2,3 STING(Stimulator of interferon genes),a crucial immune adapter functioning in host cells,mediates cGAS(Cyclic GMP-AMP Synthase)sensing of exogenous and endogenous DNA fragments and generates innate immune responses.4 Whether STING activation was involved in infection and replication of enterovirus remains largely unknown.In the present study,we discovered that human enterovirus A71(EV-A71)infection triggered STING activation in a cGAS dependent manner.EV-A71 infection caused mitochondrial damage and the discharge of mitochondrial DNA into the cytosol of infected cells.However,during EV-A71 infection,cGAS-STING activation was attenuated.EV-A71 ^(pro)teins were screened and the viral ^(pro)tease 2A^(pro) had the greatest capacity to inhibit cGAS-STING activation.We identified TRAF3 as an important factor during STING activation and as a target of 2A^(pro).Supplement of TRAF3 rescued cGAS-STING activation suppression by 2A^(pro).TRAF3 supported STING activation mediated TBK1 phosphorylation.Moreover,we found that 2A^(pro) ^(pro)tease activity was essential for inhibiting STING activation.Furthermore,EV-D68 and CV-A16 infection also triggered STING activation.The viral ^(pro)tease 2A^(pro) from EV-D68 and CV-A16 also had the ability to inhibit STING activation.As STING activation prior to EV-A71 infection generated cellular resistance to EV-A71 replication,blocking EV-A71-mediated STING suppression represents a new anti-viral target.
文摘The advent of tyrosine kinase inhibitor(TKI)therapy markedly improved the outcome of patients with chronic-phase chronic myeloid leukemia(CML).However,the poor prognosis of patients with advanced-phase CML and the lifelong dependency on TKIs are remaining challenges;therefore,an effective therapeutic has been sought.The BCR–ABL p210 fusion protein’s junction region represents a leukemia-specific neoantigen and is thus an attractive target for antigen-specific T-cell immunotherapy.BCR–ABL p210 fusion-region-specific CD4+T-helper(Th)cells possess antileukemic potential,but their function remains unclear.In this study,we established a BCR–ABL p210 b3a2 fusion-region-specific CD4+Th-cell clone(b3a2-specific Th clone)and examined its dendritic cell(DC)-mediated antileukemic potential.The b3a2-specific Th clone recognized the b3a2 peptide in the context of HLA-DRB1*09:01 and exhibited a Th1 profile.Activation of this clone through T-cell antigen receptor stimulation triggered DC maturation,as indicated by upregulated production of CD86 and IL-12p70 by DCs,which depended on CD40 ligation by CD40L expressed on b3a2-specific Th cells.Moreover,in the presence of HLA-A*24:02-restricted Wilms tumor 1(WT1)235–243 peptide,DCs conditioned by b3a2-specific Th cells efficiently stimulated the primary expansion of WTI-specific cytotoxic T lymphocytes(CTLs).The expanded CTLs were cytotoxic toward WT1235–243-peptide-loaded HLA-A*24:02-positive cell lines and exerted a potent antileukemic effect in vivo.However,the b3a2-specific Th-clone-mediated antileukemic CTL responses were strongly inhibited by both TKIs and interferon-α.Our findings indicate a crucial role of b3a2-specific Th cells in leukemia antigen-specific CTL-mediated immunity and provide an experimental basis for establishing novel CML immunotherapies.
基金Supported by the National Natural Science Foundation of China(No.81360258,81260463)the Natural Science Foundation of Guangxi Province(No.2014GXNSFAA118175)。
文摘Objective:To investigate the impacts of two herbal preparations for human immunodeficiency virus/aquired immune deficiency syndrome(HIV/AIDS)patients,Shenling Fuzheng Capsule(参灵扶正胶囊,SLFZC)and Qingdu Capsule(清毒胶囊,QDC),on the efficacy of highly active antiretroviral therapy(HAART).Methods:HIV/AIDS patients met the criteria were all enrolled in a 1-year cohort study,in which patients receiving HAART alone were designated as Group A,those receiving HAART in combination with SLFZC were designated as Group B,and those receiving HAART in combination with QDC were designated as Group C,100 cases in each group.The dose of SLFZC was 1.48 g(4 capsules),3 times daily,and QDC 1.56 g(4 capsules),3 times daily.T cell subsets,HIV RNA and HIV-1 drug resistance were detected at enrollment and 1 year after treatment.Patients were followed up every 3 months,during which side-effects and other clinical data were recorded.Results:After 1-year treatment,the median increment in CD4 counts was 165.0,178.0 and 145.0 cells/μL for Group A,B and C,respectively.HIV RNA was undetectable in 94%of patients in Group A,96%in Group B and 92%in Group C.There were no differences regarding the increment in CD4 counts,HIV RNA and frequency of HIV-1 drug resistance mutations.Two of the 14 suspected side-effect symptoms,i.e.fatigue and dizziness,were lower in Groups B and C than in Group A(P<0.05,respectively).Conclusion:SLFZC and QDC do not have a negative impact on immunological and virological response to HAART;however,these preparations are not as potent in reducing HAART-associated side-effects as anticipated.
基金F.K.was funded by a scholarship from the NIH Fogarty International Center grants D43-TW000011 and D43-TW009780.E.J.A.was funded by NIAID/NIH AI49170holds the Canada Research Chair in HIV-1 Pathogenesis and Viral Control.M.E.Q-M was partially supported by the CWRU/UH Center for AIDS Research(P30 AI036219)by funding from University Hospitals Cleveland Medical Center(UHCMC)for the University Hospitals Translational Laboratory(UHTL).
文摘Background:Thymidine analogs,namely AZT(Zidovudine or Retrovir^(TM))and d4T(Stavudine or Zerit^(TM))are antiretroviral drugs still employed in over 75%of first line combination antiretroviral therapy(cART)in Kampala,Uganda despite aversion to prescribing these drugs for cART in high income countries due in part to adverse events.For this study,we explored how the continued use of these thymidine analogs in cART could impact emergence of drug resistance and impact on future treatment success in Uganda,a low-income country.Methods:We examined the drug resistance genotypes by Sanger sequencing of 262 HIV-infected patients failing a first line combined antiretroviral treatment containing either AZT or d4T,which represents approximately 5%of the patients at the Joint Clinical Research Center receiving a AZT or d4T containing treatment.Next generation sequencing(DEEPGEN^(TM)HIV)and multiplex oligonucleotide ligation assays(AfriPOLA)were then performed on a subset of patient samples to detect low frequency drug resistant mutations.CD4 cell counts,viral RNA loads,and treatment changes were analyzed in a cohort of treatment success and failures.Results:Over 80%of patients failing first line AZT/d4T-containing cART had predicted drug resistance to 3TC(Lamivudine)and non-nucleoside RT inhibitors(NNRTIs)in the treatment regimen but only 45%had resistance AZT/d4T associated resistance mutations(TAMs).TAMs were however detected at low frequency within the patients HIV quasispecies(1-20%)in 21 of 34 individuals who were failing first-line AZT-containing cART and lacked TAMs by Sanger.Due to lack of TAMs by Sanger,AZT was typically maintained in second-line therapies and these patients had a low frequency of subsequent virologic success.Conclusions:Our findings suggest that continued use of AZT and d4T in first-line treatment in low-to-middle income countries may lead to misdiagnosis of HIV-1 drug resistance and possibly enhance a succession of second-and third-line treatment failures.
基金This research was supported in part by a grant-in-aid for scientific research from the Ministry of Education,Science,Sports,and Culture of Japan,by a grant from Human Science Foundation,and by a grantin-aid for AIDS research from the Ministry of Health,Labor,and Welfare of Japan.
文摘Untreated human immunodeficiency virus(HIV)infections usually lead to death from AIDS,although the rate of the disease progression varies widely among individuals.The cytotoxic T lymphocyte(CTL)response,which is restricted by highly polymorphic MHC class I alleles,plays a central role in controlling HIV replication.It is now recognized that the antiviral efficacy of CTLs at the single cell level is dependent on their antigen specificity and is important in determining the quality of host response to viruses so that the individual will remain asymptomatic.However,because of the extreme mutational plasticity of HIV,HIV-specific CTL responses are continuously and dynamically changing.In order to rationally design an effective vaccine,the questions as to what constitutes an effective antiviral CTL response and what characterizes a potent antigenic peptide to induce such responses are becoming highlighted as needing to be answered.
基金supported by funds from the National Key R&D Program of China (2022YFE0203100)the CAMS Innovation Fund for Medical Sciences (CIFMS 2021-I2M-1-038 and CIFMS 2022-I2M-1-021)the National Natural Science Foundation of China (82271802,82241075,and 82072288).
文摘Monkeypox(mpox)outbreak in 2022 has caused more than 91,000 cases,has spread to 115 countries,regions,and territories,and has thus attracted much attention.The stability of poxvirus particles in the environment is recognized as an important factor in determining their transmission.However,few studies have investigated the persistence of poxviruses on material surfaces under various environmental conditions,and their sensitivity to biocides.Here,we systematically measured the stability of vaccinia virus(VACV)under different environmental conditions and sensitivity to inactivation methods via plaque assay,quantitative real‐time polymerase chain reaction(qPCR),and Gaussia luciferase(G‐luciferase)reporter system.The results show that VACV is stable on the surface of stainless steel,glass,clothing,plastic,towel,A4 paper,and tissue and persists much longer at 4℃ and?20℃,but is effectively inactivated by ultraviolet(UV)irradiation,heat treatment,and chemical reagents.Our study raises the awareness of long persistence of poxviruses in the environment and provides a simple solution to inactivate poxviruses using common disinfectants,which is expected to help the control and prevention of mpox virus and future poxvirus outbreaks.
文摘Background andAims:Hepatitis C Virus(HCV)is uniformly recurrent after liver transplant(LT)and recurrence is associated with an increased risk of mortality.Immunosuppressive medications increase the risk of chronic kidney disease,and the presence of chronic kidney disease presents a challenge for HCV treatment in LT recipients.The aim of this study was to assess changes in glomerular filtration rates(GFRs)of LT recipients receiving HCV treatment.Methods:This is a retrospective study of LT patients who received HCV treatment between 2015 and 2016(n=60).The outcomes of interest were differences in serum creatinine levels and in GFR,measured at treatment initiation and at 24 weeks after treatment.The average age of the patients was 59 years-old,and 17%were cirrhotic and 67%were treatment-experienced.All patients received sofosbuvir/ledipasvir without ribavirin.Results:All patients achieved sustained virologic response at 12 weeks after treatment(SVR12).At baseline,55%of patients had GFR<60 mL/min per 1.73 m2.Among those patients,GFR did not change in 18%,33%had improved GFR,and 48%had worsened GFR.Up to 45%of the patients had a GFR>60 mL/min per 1.73 m2.Among those patients,GFR did not change in 81%,and 19%had worsened GFR.In the entire cohort,65%of patients had improved or stable GFR and 35%had worsened GFR.The average change in serum creatinine between baseline and 24 weeks was 0.10(p=0.18).Conclusions:This study showed improved or unchanged GFR in 65%and worsened GFR in 35%of LT recipients who achieved SVR12.Worsening of GFR was more frequently encountered in those with impaired renal function at baseline.Caution should be used when treating HCV in LT recipients,especially those with baseline status of renal impairment.
文摘COVID-19 is another major pandemic of viral infectious disease in the 21st century. Since the first case was reported in Wuhan, China, in December 2019, COVID-19 has resulted in more than 100 million confirmed cases and more than 2 million deaths. COVID-19 has been considered to be a systemic inflammatory response syndrome caused by SARS-CoV-2 infection, mainly with pulmonary lesions. Most patients have mild symptoms and a good prognosis, but severe or critical cases can lead to death. Otherwise, there is no effective antiviral drug to treat COVID-19.
