长期抗病毒治疗HIV-1感染者T细胞的线粒体氧化磷酸化特点

目的 分析长期抗病毒治疗的HIV-1感染者T淋巴细胞中线粒体质量和氧化磷酸化水平,探讨其与主要临床指标的关系及临床意义.方法 本研究入组20例健康对照(HCs)和67例ART时间大于2年的HIV-1感染者,其中完全免疫应答者(CRs)29例,免疫无应答者(INRs)38例.通过流式细胞术检测CD4、CD8细胞线粒体质量...     

抗病毒治疗HIV-1感染者外周血CD39~+ NK细胞的表达特点

目的通过分析接受长期抗病毒治疗(ART)的1型艾滋病病毒(HIV-1)感染者体内CD39~+NK细胞的频率和表型特征,探索其与主要临床指标的关系及临床意义。方法本研究入组10例健康对照(HCs)和28例长期接受ART的HIV-1感染者。利用流式细胞术检测NK细胞亚群分布以及NK细胞上CD39的表达情况,分析CD39+NK细胞亚群比例与CD4、CD8~+T淋巴细胞(简称CD4、CD8细胞)计数、以及CD4/CD8细胞比值的相关性。结果 28例长期接受ART的HIV-1感染者中,18例免疫重建成功患者(CRs)和10例免疫重建失败患者(INRs)。相较于HCs和CRs组,INRs组CD56dim亚群比例明显下降(平均值94.75%vs.82.65%,P 0.01;平均值93.20%vs.82.65%,P 0.001);INRs组CD39~+NK细胞的频率明显高于CRs组(平均值21.45%vs.7.79%,P 0.05)和HCs组(平均值21.45%vs.4.115%,P 0.001);长期接受ART的HIV-1感染者CD39+NK细胞占比与其CD4/CD8细胞比值呈负相关(r=-0.392 4,P=0.038 9)。结论免疫重建失败患者外周血中CD39+NK细胞表达频率明显高于免疫重建成功患者,HIV-1慢性感染者外周血CD39~+NK细胞表达增加伴随着CD4/CD8细胞比值的降低。     

HIV-1感染相关自身免疫性疾病的研究进展

随着抗反转录病毒治疗(ART)的问世,1型艾滋病病毒(HIV-1)感染者的生存时间明显延长,非HIV定义性疾病的发病率增加,其中自身免疫性疾病(AID)的发生逐渐引起人们的重视。HIV-1慢性感染造成宿主免疫系统紊乱,影响着患者AID的发生率;ART使宿主免疫得到恢复,对不同的AID的进展和预后影响各异。与单纯的AID相比,HIV-1感染相关的AID在治疗方面也有许多不同。针对这些问题,本文在介绍HIV-1与AID的总体情况基础上,阐述HIV-1合并不同AID的特点,同时分析可能的发病机制,最后对HIV-1感染相关的AID的管理与治疗进行了展望。     

HIV-1感染中的白介素-2免疫治疗作用

抗反转录病毒治疗（ART）开始的时机越来越早,但总有免疫重建失败或者Ⅰ型艾滋病病毒（HIV-1）潜伏感染灶无法清除的情况,因此白介素-2（IL-2）目前被广泛研究用于辅助ART治疗、加强免疫重建或者活化潜伏感染的HIV-1。目前比较确定的是：（1）IL-2能延长CD4＋T细胞的半衰期,增加CD4＋T细胞的数量;（2）IL-2合并ART与单独使用ART相比,不能减少HIV-1相关的机会性感染或死亡,临床应用着重于活化HIV-1储存库细胞;（3）IL-2合并ART能有效增加HIV-1储存库细胞的消减速率,外周循环中HIV-1感染的处于静止状态的记忆T细胞数量下降,甚至检测不出来;（4）IL-2的临床应用趋向周期性使用和长期使用。     

调节性T细胞稳态与慢性HIV-1感染引起的异常免疫活化研究

目的本研究旨在探讨CD4＋Foxp3＋调节性T细胞（regulatory Tcells,Treg）稳态与慢性HIV-1感染者疾病进程及免疫活化的相关性。方法选择50例慢性HIV-1感染者,包括AIDS患者15例（AIDS组）、典型进展（typical progressor,TP）患者25例（TP组）、长期非进（long-term non-progressor,LTNP）患者10例（LTNP组）,另选健康对照者（healthy control,HC）15例（HC组）。用流式细胞仪检测Treg的增殖标志Ki-67和凋亡标志半胱氨酰天冬氨酸蛋白酶-3,同时检测Treg的活化标志CD38和人白细胞抗原-DR。结果在HC组和慢性HIV-1感染者中,Treg的增殖和凋亡速率均显著高于CD4＋Foxp3非调节性T细胞,这种稳态的改变在TP组和AIDS组中更为明显。进一步研究发现Treg增殖和凋亡与其活化程度呈正相关。结论慢性HIV-1感染导致Treg的过度活化,进而导致Treg稳态的改变。Treg稳态可以作为预测HTV/AIDS患者疾病进展的一项指标。     

PBMC HIV-1 DNA的动态监测在HIV-1感染者抗病毒治疗过程中的临床意义

目的探讨1型艾滋病病毒(HIV-1)感染者接受抗病毒治疗(ART)过程中,当获得核糖核酸(RNA)病毒学完全抑制后,患者外周血单个核细胞(PBMC)中HIV-1脱氧核糖核酸(DNA)的动态变化及其临床意义。方法分别在HIV-1感染者血浆HIV-1 RNA首次20拷贝/mL时(定义为转阴)、RNA转阴1年时、RNA转阴2年时检测患者PBMC中HIV-1 DNA的含量,比较三个时间点患者PBMC中HIV-1 DNA含量的动态变化,不同ART方案以及获得RNA病毒学完全抑制所需的时间对HIV-1感染者PBMC中HIV-1 DNA的影响。结果治疗组34例HIV-1感染者接受ART过程中,在血浆HIV-1 RNA首次转阴时、RNA转阴1年时、RNA转阴2年时三个时间点患者PBMC中HIV-1 DNA含量分别为(2.88±0.50)、(2.58±0.47)、(2.57±0.43)Log10拷贝/106个细胞,差异有统计学意义;而未接受ART的对照组15例HIV-1感染者PBMC中HIV-1 DNA含量为(3.26±0.56)Log10拷贝/106个细胞,与ART治疗组比较,差异有统计学意义;含依非韦伦的一线方案和含洛匹那韦/利托那韦的二线方案对患者PBMC中HIV-1 DNA含量的影响无明显统计学差异;HIV-1感染者获得RNA病毒学完全抑制的时间越早,其PBMC中HIV-1 DNA的水平越低。结论在ART获得RNA病毒学完全抑制的HIV-1感染者仍可检出PBMC HIV-1 DNA;随着ART延长,PBMC HIV-1 DNA逐渐消减;PBMC HIV-1 DNA检测有助于判断ART疗效。     

HIV-1慢性感染者CD39~+PD-1~+CD4~+T淋巴细胞特点与抗病毒治疗疗效的关系

目的通过分析1型艾滋病病毒(HIV-1)感染者不同疾病阶段CD39~+PD-1~+CD4~+T淋巴细胞(简称CD39~+PD-1~+CD4细胞)的特点及其与潜伏病毒库形成的关系,探讨CD39~+PD-1~+CD4细胞的临床意义。方法通过流式细胞术检测CD4细胞上CD39及PD-1的表达情况,分析CD39~+PD-1~+CD4细胞与CD4细胞计数、病毒载量及CD4细胞内病毒指标的相关性。通过实时荧光定量聚合酶链反应(PCR)检测免疫重建成功患者(CRs)和免疫重建失败患者(INRs)的HIV库,分析CD39~+PD-1~+CD4细胞与HIV库的关系。结果入组11例健康对照(HCs)和69例HIV-1感染者,其中包括38例未抗病毒治疗(ART)者(TNs)、21例CRs、10例INRs。1)与HCs相比,TNs组患者CD39~+PD-1~+CD4细胞亚群占比显著升高(平均值0.99%vs. 2.50%);与TNs组相比,ART后,CRs组患者的CD39~+PD-1~+CD4细胞亚群占比显著降低(平均值2.50%vs. 0.86%);而INRs组患者该细胞亚群占比显著高于CRs组(平均值2.74%vs. 0.86%);2)在TNs组患者中CD39~+PD-1~+CD4细胞亚群占比与CD4细胞计数呈负相关(r=-0.359 6, P=0.026 6),与病毒载量呈正相关(r=0.451 1, P=0.004 5);3)ART两年以上患者CD39~+PD-1~+CD4细胞亚群占比与HIV脱氧核糖核酸(HIV DNA)正相关(r=0.565 9,P=0.047 3),与细胞相关的未剪接HIV核糖核酸(HIV us RNA)正相关(r=0.675 8,P=0.013 7)。结论 CD39~+PD-1~+CD4细胞与ART后免疫重建失败相关,其机制可能是CD39~+PD-1~+CD4细胞促进HIV建立潜伏病毒库。     

山州某县HIV-1感染者治疗前耐药情况及影响因素分析

目的 分析凉山州某县HIV-1感染者治疗前耐药情况及影响因素，为制定针对性抗反转录病毒治疗（antiretroviral therapy, ART）方案，减少整体抗病毒治疗失败率提供理论依据。方法?选取2022年6—12月间，于凉山州某县医院就诊的拟启动ART的HIV-1感染者107例，完善治疗前耐药（pretreatment drug resistance, PDR）基因检测及HIV-1亚型检测，同时收集基线血CD4+ T细胞计数、HIV-1病毒载量及常规检查指标，分析PDR总体发生率及相关危险因素。结果?107例HIV-1感染者中基因扩增成功101例，成功率为94.4%。101例感染的HIV-1主要基因型为B+C亚型（48/101，47.5%）和CRF07_BC重组型（46/101，45.5%）。共检测出存在耐药基因突变者21例，PDR发生率为20.8%，实际耐药者11（耐药率10.9%）。核苷类逆转录酶抑制剂耐药突变1例为A62V位点。非核苷类逆转录酶抑制剂耐药突变15例，主要突变位点为K103N、Y181C、V179D及V179VD等，分别造成依非韦仑、奈韦拉平、利匹韦林、依曲韦林等药物的不同程度耐药。还有6例为整合酶抑制剂耐药突变，突变位点包含E157Q、A128T及G163R。经单因素及多因素Logistic回归分析，汉族及B+C亚型与发生PDR突变具有相关性，其中汉族为风险因素，B+C亚型为保护性因素。结论?凉山州某县初始ART的HIV-1感染者中，存在较大比例的PDR基因突变，除了常见的核苷类及非核苷类逆转录酶抑制剂耐药外还出现了整合酶抑制剂的耐药突变，应该引起高度注意。     

HIV-1感染者外周血增加的CD71~+红系细胞特点及临床意义

目的探讨HIV-1感染者外周血CD71~+红系细胞的特点及其与疾病进展的关系。方法通过流式细胞术检测HIV-1感染者外周血CD71~+红系细胞,分析其与HIV-1 RNA、CD4细胞计数、CD4/CD8细胞比值的相关性。结果入组10例健康对照(HCs)和49例HIV-1感染者,后者包括28例未接受过ART者(TNs)和21例免疫重建成功患者(CRs)。与HCs组(平均值0.69%)相比,TNs组患者CD71~+红系细胞频率明显升高(平均值2.79%)。CRs组患者经ART后,CD71~+红系细胞频率降低(平均值1.18%),但是未恢复到正常水平。TNs组患者CD71~+红系细胞频率与病毒载量呈显著正相关(r=0.503 4,P=0.006 3),与CD4/CD8细胞比值呈明显负相关(r=-0.464 0,P=0.012 9)。与HCs(平均值158 g/L)相比,TNs组患者外周血血红蛋白含量明显降低(平均值149 g/L);CRs组患者经ART后,血红蛋白含量升高(平均值154 g/L),并且恢复到正常水平;TNs组患者CD71~+红系细胞频率与血红蛋白含量呈明显负相关(r=-0.462 5,P=0.013 2)。与HCs(平均值53.84%)相比,TNs组患者CD71~+红系细胞活性氧(ROS)表达水平明显升高(平均值66.64%);CRs组患者经ART后,CD71~+红系细胞表达ROS显著降低(平均值43.82%),并且降至正常水平。结论HIV-1感染导致外周血CD71~+红系细胞频率升高,并且与疾病进展和血红蛋白的降低密切相关。     

长期不进展者抗HIV-1相关机制的研究进展

临床实践调查发现,Ⅰ型艾滋病病毒（HIV-1）感染存在不同的病程进展模式,长期不进展者（LTNPs）是指,在HIV-1感染者中,小部分未接受抗病毒治疗而保持病程长期不进展的个体。然而是什么机制使得这些HIV-1感染者疾病长期不进展？近年来有关LTNPs抗HIV-1的作用机制受到越来越多的关注。文章收集了有关LTNPs最近的研究进展,着重从机体免疫学、宿主遗传学、病毒生物学三方面进行综述。     

Dose-dependent influence of didanosine on immune recovery in HIV-infected patients treated with tenofovir

BACKGROUND: Antiretroviral therapy (ART) containing tenofovir disoproxil fumarate (TDF) and didanosine (ddI) has been associated with poor immune recovery despite virologic success. This effect might be related to ddI toxicity since ddI exposure is substantially increased by TDF. OBJECTIVE: To analyze whether immune recovery during ART with TDF and ddI is ddI-dose dependent. DESIGN AND METHODS: A retrospective longitudinal analysis of immune recovery measured by the CD4 T-cell slope in 614 patients treated with ART containing TDF with or without ddI. Patients were stratified according to the tertiles of their weight-adjusted ddI dose: low dose (< 3.3 mg/kg), intermediate dose (3.3-4.1 mg/kg) and high dose (> 4.1 mg/kg). Cofactors modifying the degree of immune recovery after starting TDF-containing ART were identified by univariable and multivariable linear regression analyses. RESULTS: CD4 T-cell slopes were comparable between patients treated with TDF and a weight-adjusted ddI-dose of < 4.1 mg/kg per day (n = 143) versus TDF-without-ddI (n = 393). In the multivariable model the slopes differed by -13 CD4 T cells/mul per year [95% confidence interval (CI), -42 to 17; P = 0.40]. In contrast, patients treated with TDF and a higher ddI dose (> 4.1 mg/kg per day, n = 78) experienced a significantly impaired immune recovery (-47 CD4 T cells/microl per year; 95% CI, -82 to -12; P = 0.009). The virologic response was comparable between the different treatment groups. CONCLUSIONS: Immune recovery is impaired, when high doses of ddI (> 4.1 mg/kg) are given in combination with TDF. If the dose of ddI is adjusted to less than 4.1 mg/kg per day, immune recovery is similar to other TDF-containing ART regimen.     

肺气肿动物模型研究进展

阻塞性肺气肿（肺气肿）是慢性阻塞性肺疾病（COPD）的主要病理表现,已成为研究中的焦点。多种实验性肺气肿动物模型的研究对揭示COPD的遗传背景、诱发因素、发病机制及新药的开发起了极大的促进作用。最近,有大量研究数据显示,细胞凋亡在COPD发病中起重要作用。本文就肺气肿动物模型的构建方法及其研究进展作一综述。     

Progressive human immunodeficiency virus-specific immune recovery with prolonged viral suppression

The degree of immune recovery achievable with anti-human immunodeficiency virus (HIV) therapy remains to be established. The effects of potent antiretroviral therapy, including ritonavir and saquinavir, on immune function were studied for a prolonged period in 41 patients. After 96 weeks, 88% of patients had plasma HIV RNA levels below the limit of quantitation. There were continuous increases in CD4 lymphocyte counts and in CD4:CD8 ratios over time. About half the patients developed lymphoproliferative responses to HIV p24 antigen, and nearly all developed responses to phytohemagglutinin. This occurred in parallel with increases in interleukin-12 production and expression of CD28 on CD8 lymphocytes, despite potential antiproliferative effects of protease inhibitors. Transient increases in virus load were temporally associated with loss of proliferative responses. The improved immune function, including HIV-specific immunity in many subjects, demonstrates the potential reversibility of HIV-induced immunodeficiency and does not identify a limit to immune recovery.     

非结核分枝杆菌相关研究新进展

非结核分枝杆菌在自然界中广泛存在,部分可引起人类疾病.因非结核分枝杆菌对多种抗结核药物耐药,且诊断困难、患者预后较差,使非结核分枝杆菌感染性疾病逐渐成为医学界十分关注的研究课题.作者从非结核分枝杆菌种类及感染率、非结核分枝杆菌耐药情况及耐药机制研究、非结核分枝杆菌感染特点及治疗方案、非结核分枝杆菌检测方法及环境水非结核分枝杆菌污染研究等方面综述了非结核分枝杆菌相关的研究进展.其耐药机制及传播机制尚未阐明,需要进行深入研究.     

Cytomegalovirus-specific immune recovery following allogeneic HLA-identical sibling transplantation with reduced-intensity preparative regimen

Cytomegalovirus (CMV) represents a major cause of morbidity after allogeneic stem cell transplantation (allo-SCT). Using interferon-gamma-enzyme-linked immunospot (ELISPOT) assay and HLA-peptide tetramers, we analysed 54 patients who received a reduced-intensity conditioning regimen, including fludarabine, busulphan and antithymocyte globulin (ATG), with the aim of defining essential elements of protective immunity to CMV. The cumulative incidence of CMV positive antigenaemia was 37% occurring at a median of 43 days (range, 7-104) after allo-SCT. In univariate analysis, conditioning regimen (ATG dose) and graft characteristics (graft source and CD3+ T-cell dose) significantly influenced CMV-specific immune recovery. A significant correlation (P=0.000002) was found between CMV-specific T cells detected by IFN-gamma ELISPOT assay and pp65-specific CD8+ T-cell frequency quantified by tetramers. CMV-specific CD8+ T cells presented a phenotype of effector cells (perforin and 2B4 positive). In multivariate analysis, bone marrow (BM) as a graft source was the only variable associated with an increased risk of CMV positive antigenaemia (P=0.0001) in line with the ELISPOT assay showing a higher frequency of functional CMV-specific effectors within peripheral blood stem cell grafts as compared to BM. Thus, early monitoring of CMV-specific immune recovery using sensitive new tools might prove useful for patient management after allo-SCT.     

Evaluation of the impact of highly active antiretroviral therapy on immune recovery in antiretroviral naive patients

Objectives To examine the extent of immune reconstitution in treatment‐naive patients with CD4 T‐cell counts <500 cells/μL following 48 weeks of highly active antiretroviral therapy (HAART). Methods Thirteen antiretroviral naive patients were evaluated longitudinally for 48 weeks on HAART utilizing immune functional and lymphocyte phenotyping assays, including lymphocyte proliferation assay, flow cytometric evaluation of cell surface markers, and delayed type hypersensitivity skin tests. Virologic responses were monitored using commercially available viral load assays and gag/pol mRNA quantification using simultaneous immunophenotyping/UltraSensitive fluorescence in situ hybridization (ViroTect In Cell HIV‐1 Detection Kit; Invirion, Frankfort, MI). Thymic function was evaluated for a subset of four patients using real‐time polymerase chain reaction (PCR) for T‐cell receptor excision circle (TREC) quantification and thymic scans using computerized axial tomography (CT) of the thymus. Results HAART initiation resulted in a significant decline in plasma viremia and percentage of infected peripheral blood cells, and a rise in CD4 T cells from a baseline median of 207 cells/μL to a week‐48 median of 617 cells/μL. The rise was predominately in CD4 memory cells. Naive T cells also increased in number, but at a slower rate. Activated (HLA‐DR CD38) CD4 and CD8 T cells were elevated at baseline (24 and 62%, respectively) and declined by week 48 (17 and 36%, respectively) but did not reach normal levels. The number of Fas CD4 T cells increased from a baseline median of 169 to 381 cells/μL at week 48. Both soluble interleukin (IL)‐2 and tumour necrosis factor (TNF) II receptors declined by week 48. HIV p24 lymphocyte proliferation assay responses were transiently detected in three patients. TREC values increased from a median 6400 copies/μg at baseline to a week‐48 median value of 26 697 copies/μg. Conclusion Immune functional reconstitution was not achieved in these HAART naive patients.     

Neuroimaging--recent issues and future progresses

Recent advances in the technology of non-invasive neuroimaging techniques, include X-ray CT, magnetic resonance imaging, positron CT, etc. The trend of neuroimaging is from the diagnosis of the brain structural change to the functional localization of the brain function with accurate topographical data. Brain activation studies disclosed the responsible regions in the brain for various kinds of paradigms, including motor, sensory, cognitive functions. Another aspect of brain imaging shows the pathophysiological changes of the neurological disorders, such as Alzheimer's disease by abnormal CBF or metabolism changes. It is very important to note that the neurotransmitter receptor imaging is now available for various kinds of transmitters. We recently developed a new tracer for nicotinic type acetylcholine receptor, which might be involved in the pathophysiology of Alzheimer's disease and its treatment. In the near future, we will be able to visualize the proteins in the brain such as amyloid protein, which will make us to diagnose Alzheimer's patients accurately, and with respect to neuroscience research, not only neuronal functional localizations but also relationship between them will become important to disclose the functional aspects of the brain.     

雌激素对成骨细胞、破骨细胞作用的新进展

成骨细胞和破骨细胞均表达雌激素受体,但雌激素对两者的作用远未阐明.雌激素能诱导成骨细胞产生骨保护素(osteoprotegerin,OPG).当雌激素缺乏时,T细胞分泌TNF和IL-7等增加,作用于破骨细胞加速骨丢失;绝经后FSH升高,可直接作用于破骨细胞增强其功能.雌激素亦可通过非基因组效应减缓成骨细胞凋亡,加速破骨细胞凋亡.最近研究发现,雌激素通过ERα可直接阻止骨丢失,可能机制是诱导成骨细胞和破骨细胞表达FasL,以旁分泌和自分泌的方式促进破骨细胞凋亡.