HIV-1感染者特异CTL反应的研究进展

艾滋病病毒I型(HIV-1)感染可以同时活化宿主的T细胞免疫与体液免疫。被活化的HIV-1特异性细胞毒性T淋巴细胞(CTL),可通过释放穿孔素和颗粒酶或细胞因子与趋化因子等途径,来直接杀伤被感染的靶细胞,或控制病毒进入靶细胞及其复制,在与HIV-1斗争中发挥着极其重要的作用。随着研究的深入,人们对机体抵御HIV-1感染的CTL细胞免疫反应的认识也逐渐加深,已经从单一功能与单一相关因素水平进展为多功能及多因素水平的分析,从而锁定真正具有免疫保护作用的CTL反应功能群,解析控制病毒血症的主要机制,以期为新型HIV疫苗的设计以及效果评价提供科学依据。文章主要就具有免疫保护作用的CTL反应的特征及CTL反应与HIV疾病进展关系的研究等最新进展加以综述。     

Th1/Th2细胞因子与肝病关系的研究新进展

辅助T细胞(helperTcell,Th)是指能帮助B细胞分化成抗体产生细胞和放大细胞免疫应答的一个细胞群,它表达CD4而不表达CD8。Th活化后可释放细胞因子,调节T细胞、B细胞、单核细胞和其他免疫细胞活性,根据产生细胞因子的不同,Th可分为Th1、Th2及Th0三型,机体对细胞内与细胞外抗原的免疫应答主要受Th1和Th2调节。活化的Th1产生白细胞介素(IL)-2、干扰素(IFN)-γ和其他免疫效应分子,可促进T细胞应答,增强细胞免疫应答,抑制抗体产生、诱导迟发型超敏反应;活化的Th2释放IL-4及IL-10等细胞因子,可使B细胞活化、促进抗体产生。Th细胞是免疫应答的中心细胞,它不但是机体免疫应答的启动细胞,而且其活性对整个免疫应答具有调节作用,如果没有Th的活化,机体就会处于无能状态。Th1与Th2之间存在相互制约或促进作用,细胞因子组成一个复杂的分子网络,参与调节炎症反应以及器官功能的自我稳定,细胞因子介导的免疫应答在肝细胞炎症坏死、病毒清除及病毒持续存在等方面的免疫机制中均起着中心作用。     

几种免疫细胞在感染HIV-1过程中的作用

随着免疫学的发展，人们发现艾滋病病毒Ⅰ型（HIV-1）感染及其疾病进展与机体内一些细胞的免疫功能有关。CD4^＋CD25^＋调节性T细胞（Tr）在机体感染免疫中具有重要作用，在人类HIV-1感染中CD4^＋CD25^＋T细胞能控制机体CD4^＋和CD8^＋T细胞的特异性抗HIV-1免疫应答，并且与HIV-1感染状态有关。在多种疾病中都发现Th1／Th2的异常转化。目前多数研究结果表明：HIV-1感染也会造成Th2的极化，并最终造成CD4^＋T细胞功能的缺失。在机体抗HIV-1感染中，树突状细胞（DC）具有双重作用，DC在HIV-1感染中的这种双重作用导致机体内DC数量减少及功能削弱。NK细胞是对抗病毒感染的第一道防线，慢性HIV-1感染会引起NK细胞群的异常。有学者报道CD56^＋CD16^＋CD3^-CD4^＋CCR5^＋／CXCR4^＋的NK细胞可被HIV-1感染，使感染者天然免疫功能低下。虽然上述这些细胞在HIV-1感染中都有各自的功能，但是作为免疫系统网络整体而言，它们功能变化导致的HIV-1感染性疾病的进展是这些细胞相互作用、相互调节、共同作用的结果。     

趋化因子CCR5、CCR2和SDF1基因多态性与HBV感染相关性初步研究

HBV引起的肝损伤和机体的免疫应答状态有关,由基因决定的免疫应答能力可以影响感染的持续性、临床症状和结局。趋化因子是低分子量的趋化性细胞因子。它募集白细胞到炎症部位,调节T细胞发育和细胞因子产生,如INF-γ。因此,趋化因子在炎症和感染中起重要作用。近年来发现,CCR5-△32、CCR2b-64I和SDFl-3’A趋化因子多态性除了作为HIV-1的协同受体影响HIV-1感染和致病进程外,还与分枝杆菌结核(Mycobacterium     

胸膜渗液中细胞活素的含量(结核性与癌性胸膜炎的比较)

细胞活素包括白细胞介素1(IL-1)、IL-2和γ-干扰素(IFN-γ),是机体对各种感染,炎症和免疫应答反应的关键性调节物。IL-1在 T 细胞活化中具有重要作用,其生物学特性及在炎症中的关键作用表明,它们参与许多疾病的病理过程.IL-2在免疫反应调节中起决定性的作用.在分裂素或抗原活化后,它诱导和维持 T 细胞的增殖,诱导细胞毒性淋巴细胞、自然杀伤细胞和淋巴细胞活素活化的杀伤细胞产生。IFN-γ不但具有抗病毒和抗细胞的活性,而且还是一个重要的免疫调节剂.腺苷脱氨酶     

HIV-1 Env蛋白与HIV-1感染

人免疫缺陷病毒Ⅰ型(HIV-1)是艾滋病的主要病原体,HIV-1 Env蛋白在病毒的感染、侵入和干扰机体免疫机能等方面发挥着重要作用,它可以干扰细胞正常的信号转导途径、导致合胞体的形成、引发细胞病变。HIV-1感染的细胞类型包括 CD_4~+辅助T细胞、单核巨噬细胞、树突状细胞、朗罕氏细胞、胎盘滋养层细胞、神经元细胞等。HIV-1感染引发的病理变化与免疫系统的变化密切相关,免疫系统的     

MicroRNAs对HIV-1复制的调节作用及应用展望

微小核糖核酸(miRNAs)一种非编码小RNAs,在1型艾滋病病毒(HIV-1)感染的发展和转归中发挥重要作用。miRNAs通过直接作用于HIV RNA,或者通过间接调节细胞辅助因子和抗病毒因子抑制病毒复制,miRNAs也可以通过调节T细胞活化促进HIV感染。本文主要回顾在HIV-1感染者体内,异常表达的miRNAs通过多种途径促进病毒感染或者维持潜伏感染,及在感染过程中的生物调节作用。进一步研究miRNAs及其作用靶点在HIV-1感染者体内的作用可能为抗病毒治疗开启一个新的窗口。     

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。     

血小板在动脉粥样硬化形成和发展中的作用

近年来的一些研究显示血小板可作为“炎症细胞” ,活化或释放的炎症介质直接参与动脉粥样硬化的形成和发展。急性冠状动脉综合征被称为动脉硬化血栓性疾病 ,因此抗血小板治疗在ACS发病中起十分重要的作用。1　血小板参与动脉粥样硬化形成和发展的机制血小板活化后释放多种炎症介质 ,它们可以 :(1)促进血小板黏附和聚集 ;(2 )促进血小板与白细胞黏附并激活后者促使白细胞与内皮细胞黏附和白细胞向血管内膜迁移 ;(3)诱导血管平滑肌细胞的迁移和增生 ;(4)活化的血小板能够表达CD15 4 ,CD15 4激活后可显著上调血管细胞黏附分子 1和细胞间黏附…     

粘膜免疫与艾滋病的预防和控制

粘膜是大多数病原微生物侵入机体的门户。粘膜免疫系统的特异和天然免疫机制阻止了绝大部分粘膜感染的发生。世界范围内约有90%的人类免疫缺陷病毒(HIV)感染是通过粘膜发生的。与HIV-1粘膜传播有关的粘膜包括泌尿生殖系统和消化系统粘膜。消化道粘膜不仅在HIV-1侵入机体的过程中作为病毒入侵的门户,而且在HIV-1感染后为病毒的繁殖提供场所。HIV-1感染导致粘膜中CD4 T淋巴细胞不断减少,可能在HIV-1感染后的病理过程中发挥重要作用。通过杀微生物制品或艾滋病疫苗阻断或限制HIV-1跨越粘膜屏障,可能是控制HIV/AIDS粘膜传播的最有效的生物学干预措施。     

Platelets and HIV-1 infection: old and new aspects

In this review we summarize the data on interaction of platelets with HIV-1 infection. Thrombocytopenia is a common finding among HIV-1 infected patients; several combined factors contribute to low peripheral platelet counts, which are present during all the stages of the disease. In addition, a relationship between platelet count, plasma viral load and disease progression has been reported, and this shows the potential influence platelets may have on the natural history of HIV-1 disease. Several lines of evidence have shown that platelets are an integral part of inflammation, and can be also potent effector cells of innate immune response as well as of adaptive immunity. Thus, we rewieved the role of inflammatory cytokines, and chemokines as activators of platelets during HIV-1 infection. Moreover, platelets show a direct interaction with HIV-1 itself, through different pathogenic mechanisms as binding, engulfment, internalisation of HIV-1, playing a role in host defence during HIV-1 infection, by limiting viral spread and probably by inactivating viral particles. Platelets may also play an intriguing role on endothelial dysfunction present in HIV-1 infection, and this topic begins to receive systematic study, inasmuch as interaction between platelets and endothelial cells is important in the pathogenesis of atherosclerosis in HIV-1 infected patients, especially in those patients treated with antiretroviral drugs. Finally, this review attempts to better define the state of this emerging issue, to focus areas of potential clinical relevance, and to suggest several directions for future research.     

HBV pathogenesis in animal models: recent advances on the role of platelets

Hepatitis B virus (HBV) causes acute and chronic necroinflammatory liver diseases and hepatocellular carcinoma (HCC). HBV replicates noncytopathically in the hepatocyte, and most of the liver injury associated with this infection reflects the immune response. While the innate immune response may not contribute significantly to the pathogenesis of liver disease or viral clearance, the adaptive immune response, particularly the cytotoxic T lymphocyte (CTL) response, contributes to both. Recent observations also reveal that antigen-nonspecific inflammatory cells enhance CTL-induced liver pathology and, more surprisingly, that platelets facilitate the intrahepatic accumulation of CTLs, suggesting that the host response to HBV infection is a highly complex but coordinated process. The notion that platelets contribute to liver disease and viral clearance by promoting the recruitment of virus-specific CTLs into the liver is a new concept in viral pathogenesis, which may prove useful to implement treatments of chronic HBV infection in man.     

Negative correlation between blood cell counts and serum neopterin concentration in patients with HIV-1 infection.

Hematopoietic disturbances are common in patients with HIV-1 infection. Recent studies on immune activation markers such as neopterin demonstrate that HIV-1 infection is associated with chronic immune activation. We investigated a possible association between serum neopterin concentrations and blood cell counts (CD4+ T cells, white blood cells, platelets, red blood cells) and hemoglobin and hematocrit in 94 HIV-1-seropositive individuals [52 Walter Reed (WR) stage 1, 31 WR2, one WR5, and 10 WR6]. There were significant negative correlations between neopterin concentrations and CD4+ T cells, hemoglobin, hematocrit and platelets. These correlations were also significant if either only WR1 and WR2 patients or the entire set of data were considered for calculations. Thus, hematological abnormalities are associated with chronic immune activation in patients with HIV-1 infection. Large amounts of neopterin are released by human macrophages on stimulation with interferon-gamma (IFN gamma), and tumor necrosis factor alpha (TNF alpha) further enhances the effect of IFN gamma. Therefore, our data suggest that activated immune cells and specific cytokines such as IFN gamma and TNF alpha are involved inhibiting hematopoiesis.     

Identification of the platelet-derived chemokine CXCL4/PF-4 as a broad-spectrum HIV-1 inhibitor

The natural history of HIV-1 infection is highly variable in different individuals, spanning from a rapidly progressive course to a long-term asymptomatic infection. A major determinant of the pace of disease progression is the in vivo level of HIV-1 replication, which is regulated by a complex network of cytokines and chemokines expressed by immune and inflammatory cells. The chemokine system is critically involved in the control of HIV-1 replication by virtue of the role played by specific chemokine receptors, most notably CCR5 and CXCR4, as cell-surface coreceptors for HIV-1 entry; hence, the chemokines that naturally bind such coreceptors act as endogenous inhibitors of HIV-1. Here, we show that the CXC chemokine CXCL4 (PF-4), the most abundant protein contained within the α-granules of platelets, is a broad-spectrum inhibitor of HIV-1 infection. Unlike other known HIV-suppressive chemokines, CXCL4 inhibits infection by the majority of primary HIV-1 isolates regardless of their coreceptor-usage phenotype or genetic subtype. Consistent with the lack of viral phenotype specificity, blockade of HIV-1 infection occurs at the level of virus attachment and entry via a unique mechanism that involves direct interaction of CXCL4 with the major viral envelope glycoprotein, gp120. The binding site for CXCL4 was mapped to a region of the gp120 outer domain proximal to the CD4-binding site. The identification of a platelet-derived chemokine as an endogenous antiviral factor may have relevance for the pathogenesis and treatment of HIV-1 infection.     

HIV-1-suppressive factors are secreted by CD4+ T cells during primary immune responses

CD4+ T cells are required for immunity against many viral infections, including HIV-1 where a positive correlation has been observed between strong recall responses and low HIV-1 viral loads. Some HIV-1-specific CD4+ T cells are preferentially infected with HIV-1, whereas others escape infection by unknown mechanisms. One possibility is that some CD4+ T cells are protected from infection by the secretion of soluble HIV-suppressive factors, although it is not known whether these factors are produced during primary antigen-specific responses. Here, we show that soluble suppressive factors are produced against CXCR4 and CCR5 isolates of HIV-1 during the primary immune response of human CD4+ T cells. This activity requires antigenic stimulation of na?ve CD4+ T cells. One anti-CXCR4 factor is macrophage-derived chemokine (chemokine ligand 22, CCL22), and anti-CCR5 factors include macrophage inflammatory protein-1 alpha (CCL3), macrophage inflammatory protein-1 beta (CCL4), and RANTES (regulated upon activation of normal T cells expressed and secreted) (CCL5). Intracellular staining confirms that CD3+CD4+ T cells are the source of the prototype HIV-1-inhibiting chemokines CCL22 and CCL4. These results show that CD4+ T cells secrete an evolving HIV-1-suppressive activity during the primary immune response and that this activity is comprised primarily of CC chemokines. The data also suggest that production of such factors should be considered in the design of vaccines against HIV-1 and as a mechanism whereby the host can control infections with this virus.     

Platelet toll-like receptors are crucial sensors of infectious danger moieties

In addition to their haemostatic role and function in the repair of damaged vascular epithelium, platelets play a defensive role in innate immunity, having the capacity to produce and secrete various anti-infectious factors, as well as cytokines, chemokines and related products, to interact with other immune cells to modulate immune responses to pathogens. Thus, it is now widely acknowledged that platelets participate in inflammatory processes and infection resolution, most notably by expressing and using receptors to bind infectious pathogen moieties and contributing to pathogen clearance. The ability of platelets to sense external danger signals relates to the expression of certain innate immunity receptors, such as toll-like receptors (TLRs), and the activation of efficient cell signalling machinery. TLR engagement triggers platelet response, which results in adapted degranulation according to: the type of TLR engaged, the nature of the ligand and the milieu; together, the TLR-mediated event and other signalling events may be followed by aggregation. Platelets thus use complex tools to mediate a whole range of functions upon sensing danger. By linking the inflammatory and haemostatic platelet response to infection, TLRs play a central role. The extent of the inflammatory response to pathogen clearance is still a debatable issue and is discussed in this short review.     

Identification of talin head domain as an immunodominant epitope of the antiplatelet antibody response in patients with HIV-1-associated thrombocytopenia

HIV-1-associated thrombocytopenia (HIV-1-ITP) is a common complication of HIV-1 infection, frequently caused by increased peripheral platelet destruction mediated by antiplatelet antibodies (Abs) and/or platelet-bound immune complexes. Little is known about the specificity of the antiplatelet Abs at a molecular level. Here, we used immunoglobulin G (IgG) phage-display libraries generated from 3 HIV-1-ITP patients to isolate a large panel of human monoclonal antiplatelet Abs by selection on unfixed platelets. The platelet antigen recognized by all the cloned Abs was identified to be the talin head domain (talin-H), a cleavage product of talin that can be generated by platelet activation or HIV-1 protease. Talin-H was found in HIV-1-ITP-circulating immune complexes, and antitalin Abs were detected in HIV-1-ITP sera but not in controls. The cloned anti-talin-H IgGs were highly somatically mutated, indicative of an antigen-driven, affinity-matured response. These findings suggest that talin-H Ab may be a marker of HIV-1-ITP elicited due to exposure of immunodominant epitopes on talin-H as a result of a disease-related process. Abs to talin-H and related immune complexes (ICs) may contribute to HIV-1-ITP.     

Impaired survival of bone marrow GPIIb/IIIa+ megakaryocytic cells as an additional pathogenetic mechanism of HIV-1-related thrombocytopenia

Glycoproteic (GP) IIb/IIIa⁺ megakaryocytic cells were purified from the bone marrow (BM) of 15 HIV-1 seropositive thrombocytopenic patients, eight HIV-1 seronegative patients affected by immune thrombocytopenic purpura (ITP) and 14 HIV-1 seronegative normal donors. The presence of apoptosis was evaluated in freshly isolated GPIIb/IIIa⁺ cells by flow cytometry after propidium iodide staining and electron microscopy. GPIIb/IIIa⁺ cells from HIV-1 seropositive thrombocytopenic patients showed a significant (  P  < 0.001) increase of apoptosis with respect to both HIV-1 seronegative ITP patients and normal donors. Moreover, the degree of apoptosis in bone marrow GPIIb/IIIa⁺ cells purified from HIV-1 seropositive thrombocytopenic patients was inversely (  P  < 0.01) related to the count of circulating platelets, whereas it did not show any significant correlation with the absolute number of circulating CD4 T cells, the CD4/CD8 ratio or the presence of proviral gag DNA sequences. Therefore neither an advanced stage of HIV-1 disease nor a direct infection with HIV-1 seems to play a primary role in the impaired survival of BM GPIIb/IIIa⁺ megakaryocytic cells. These findings strengthen the notion that, besides the immune targeting of peripheral platelets, an impairment of the bone marrow megakaryocyte compartment may also contribute to the pathogenesis of HIV-1 related thrombocytopenia.     

Mechanisms of neuronal injury and death in HIV-1 associated dementia

Infection with the human immunodeficiency virus-1 (HIV-1) and acquired immunodeficiency syndrome (AIDS) remain a persistent and even growing health problem worldwide. Besides its detrimental systemic effects on the immune system, HIV-1 seems to enter the brain very soon after peripheral infection and can induce severe and debilitating neurological problems that include behavioral abnormalities, motor dysfunction and frank dementia. Infected peripheral immune cells, in particular macrophages, appear to infiltrate the CNS and provoke a neuropathological response involving all cell types in the brain. Both viral and host factors, such as the viral strain and the response of the host's immune system, strongly influence the course of HIV-1 disease. Moreover, HIV-1-dependent disease processes in the periphery have a substantial effect on the pathology developing in the central nervous system (CNS), although the brain eventually harbors a distinctive viral population of its own. In the CNS, HIV-1 also initiates activation of chemokine receptors, inflammatory mediators, extracellular matrix-degrading enzymes and glutamate receptor-mediated excitotoxicity, all of which can activate numerous downstream signaling pathways and disturb neuronal and glial function. Although there have been substantial improvements in the control of viral infection in the periphery, an effective therapy for HIV-1 associated dementia (HAD) is still not in sight. This article will review recently identified injurious mechanisms potentially contributing to neuronal death in association with HIV-1 disease and discuss recent and prospective approaches for therapy and prevention of HAD.     

Gut mucosal T cell responses and gene expression correlate with protection against disease in long-term HIV-1-infected nonprogressors

Limited information is available on the molecular mechanisms by which long-term HIV-1-infected nonprogressors suppress HIV-1 infection and maintain immune functions. The intestinal mucosal immune system is an early target for HIV-1 infection and severe CD4+ T cell depletion. We evaluated mucosal T lymphocyte subsets, virus-specific cellular responses, gene expression profiles, and viral loads in intestinal mucosal biopsies of long-term nonprogressor (LTNP) patients as compared to chronically HIV-1-infected patients with high viral loads (HVLs) and CD4+ T cell loss, as well as HIV-seronegative healthy individuals. This study aims to identify the mucosal correlates of HIV disease progression and to determine the molecular changes associated with immune and intestinal dysfunction. LTNP patients had undetectable viral loads, normal CD4+ T cell levels, and virus-specific cellular responses in peripheral blood and mucosal compartments. Microarray analysis revealed a significant increase in gene expression regulating immune activation, cell trafficking, and inflammatory response in intestinal mucosa of HVL patients as compared to LTNP patients. Genes associated with cell cycle regulation, lipid metabolism, and epithelial cell barrier and digestive functions were down-regulated in both HVL and LTNP patients. This may adversely influence nutrient adsorption and digestive functions, with the potential to impact the efficacy of antiretroviral therapy. We demonstrate that the maintenance of mucosal T cells, virus-specific responses, and distinct gene expression profiles correlate with clinical outcome in LTNP patients. However, the intestinal mucosal immune system remains an important target of HIV-1 infection in LTNP, and these effects may ultimately contribute toward disease progression.