Prostaglandin E2 induces the expression of functional inhibitory CD94/NKG2A receptors in human CD8+ T lymphocytes by a cAMP-dependent protein kinase A type I pathway

The CD94/NKG2A heterodimer is a natural killer receptor (NKR), which inhibits cell-mediated cytotoxicity upon interaction with MHC class I gene products. It is expressed by NK cells and by a small fraction of activated T cells, predominantly of CD8+ phenotype. Abnormal upregulation of the CD94/NKG2A inhibitory NKR on cytotoxic T cells (CTLs) could be responsible for a failure of immunosurveillance in cancer or HIV infection. In an attempt to identify the mechanisms leading to inhibitory NKR upregulation on T cells, we analyzed the expression of the CD94/NKG2A heterodimer on human CTLs activated with anti-CD3 mAb in the presence of PGE2 or with 8-CPT-cAMP, an analogue of cyclic AMP. As previously described, anti-CD3 mAb-mediated activation induced the expression of CD94/NKG2A on a small fraction of CD8+ T cells. Interestingly, when low concentrations of PGE2 or 8-CPT-cAMP were present during the culture, the proportion of CD8+ T cells expressing CD94/NKG2A was two- to five-fold higher. This upregulation was partially prevented by PKA inhibitors, such as KT5720 and Rp-8-Br-cAMP (type I selective). We also report that cAMP induces upregulation of NKG2A at the mRNA level. We further demonstrated that cross-linking of CD94 on CD8+ T cells expressing the CD94/NKG2A heterodimer inhibits their cytotoxic activity in a bispecific antibody redirected lysis assay. Our findings clearly demonstrate that the PGE2/cAMP/PKA type I axis is involved in the expression of CD94/NKG2A receptor on human CD8+ T lymphocytes.     

Modulation of 17beta-estradiol on the number and cytotoxicity of NK cells in vivo related to MCM and activating receptors

Natural killer (NK) cells are key components of immune systems and their activities could be regulated by sex hormones. In the present study we investigate the effects of estrogen on the number and cytotoxic activity of NK cells in vivo. The number and cytotoxicity of NK cells in four groups (control, sham+vehicle, Ovx+vehicle and Ovx+E2) were determined. The results showed that 17beta-estradiol (E2) increased the number of NK cells, but reduced their cytotoxicity. The increase of NK cells proportions by E2 may be mediated by up-regulating the expression of MCM7 and MCM10 proteins, which are required for DNA replication licensing in cell proliferation. The suppressed cytotoxicity of splenic NK cells by E2 may be attributable to the down-regulation of NK cells activating receptors-CD69, NKp46, NKG2DL and 2B4 (CD244), which directly inhibited NK cell activation, resulting in the reduced secretion of the soluble factors-granzyme B and FasL. INF-gamma might also act as a negative regulator in the low cytotoxicity of NK cells. In addition, the number of the NK cells is not parallel to their cytotoxicity with a long-term exposure to E2 in vivo. These results suggest that E2-mediated low cytotoxicity of NK cells may regulate host immune response in pregnancy and some female predominant diseases.     

Phenotypic and functional assessments of immune status in the rat spleen following acute heroin treatment

Heroin use is associated with an increased incidence of several types of infections, including HIV. Yet few studies have assessed whether heroin produces pharmacological alterations of immune status that might contribute to the increased rate of infections amongst heroin users. The present study investigated whether a single administration of heroin to rats produces dose-dependent alterations in functional measures of immune status and in the distribution of leukocyte subsets in the spleen. The results showed that heroin produces a dose-dependent, naltrexone-reversible suppression of the concanavalin A-stimulated proliferation of T cells, lipopolysaccharide-stimulated proliferation of B cells, production of interferon-gamma and cytotoxicity of natural killer (NK) cells in the spleen. Heroin's suppressive effect on NK cell activity results in part from a heroin-induced decrease in the relative number of NKR-P1A(hi) CD3- NK cells in the spleen. Heroin also decreases the percent of a splenic granulocyte subset, the CD11b/c+ HIS48(hi) cells, whose function currently is unknown. In contrast, heroin does not alter relative numbers of CD4+ CD3+ T cells, CD8+ CD3+ T cells, CD45+ B cells, NKR-P1A(lo) CD3+ T cells, CD11b/c+ ED1+ (or CD11b/c+ HIS48-) monocytes/macrophages or CD11b/c+ ED1- (or CD11b/c+ HIS48+) total granulocytes in the spleen. Collectively, these findings demonstrate that heroin produces pharmacological effects on functional and phenotypic measures of immune status.     

NK cell-based immunotherapies against tumors

Natural killer (NK) cells provide the first line of defence against pathogens and tumors. Their activation status is regulated by pro-inflammatory cytokines and by ligands that either target inhibitory or activating cell surface receptors belonging to the immunoglobulin-like, C-type lectin or natural cytotoxicity receptor families. Apart from non-classical HLA-E, membrane-bound heat shock protein 70 (Hsp70) has been identified as a tumor-specific recognition structure for NK cells expressing high amounts of the C-type lectin receptor CD94, acting as one component of an activating heterodimeric receptor complex. Full-length Hsp70 protein (Hsp70) or the 14-mer Hsp70 peptide T-K-D-N-N-L-L-G-R-F-E-L-S-G (TKD) in combination with pro-inflammatory cytokines enhances the cytolytic activity of NK cells towards Hsp70 membrane-positive tumors. Based on these findings cytokine/TKD-activated NK cells were adoptively transferred in tumor patients. These findings were compared to results of clinical trials using cytokine-activated NK cells.     

CD59在艾滋病感染者CD4^＋T细胞表达及凋亡的影响

目的探讨补体调节蛋白CD59在艾滋病（HIV）感染者外周血CD4^＋T细胞上的表达及与凋亡之间的关系。方法收集12例确诊HIV感染者外周血标本（观察组）,同时收集10例健康对照者外周血标本（对照组）。分离外周血单个核细胞（PBMC）,并进行细胞表面染色。使用BDFACSCanto流式仪检测各项指标,采用FACSDiva软件分析CD4^＋T细胞CD59的表达情况,并分析CD59^＋CD4^＋T、CD59^-CD4^＋T细胞的凋亡情况。结果观察组CD4^＋T细胞CD59表达明显高于对照组（t=5．198,P〈0．01）;CD59＋CD4^＋细胞凋亡比率明显升高（t=5．968,P〈0．01）;而CD59^-CD4^＋T细胞的凋亡比例二组间差异无统计学意义（t=0．1353,P=0．8577）。结论HIV感染可引起CD4^＋T细胞补体调节蛋白CD59的表达,而CD59的表达会使CD4^＋T细胞凋亡增加。     

Synergistic cytotoxicity of ex vivo expanded natural killer cells in combination with monoclonal antibody drugs against cancer cells

The adoptive transfer of highly cytotoxic natural killer (NK) cells is an emerging tool for cancer immunotherapy. Antibody-dependent cellular cytotoxicity (ADCC) has recently been identified as one of the critical factors for the clinical efficacy of anticancer antibodies, in which NK cells are the major effectors of ADCC. NK cells were expanded from PBMC by a feeder-cell-free expansion method. NK cell expansion efficiency was evaluated within a period of 21 days. The kinetics of NK cell expansion and the expression of activating and inhibitory receptors on NK cells were monitored. NK cells producing IFN-γ and TNF-α were detected by intracellular cytokine staining. The cytotoxicity of expanded NK cells against various cancer cells was compared with that of freshly isolated NK cells. The ADCC functions of expanded NK cells in combination with rituximab against CD20 + lymphoma cell lines were evaluated. Our method efficiently expanded NK cells ex vivo, which showed a much higher activity to induce the expression of activating receptors and to produce IFN-γ and TNF-α as well as cytotoxicity against various cancer cell lines including CD133 + primary cancer cells than freshly isolated NK cells. We observed a synergistic cytotoxicity of our expanded NK cells against CD20 + B lymphoma cell lines as well as higher IFN-γ and TNF-α production when combined with rituximab. Our results suggest that the adoptive transfer of a large number of ex vivo expanded NK cells, particularly in combination with monoclonal antibody drugs, is a useful tool for cancer immunotherapy.     

Mechanism of activation of human peripheral blood NK cells at the single cell level by Echinacea water soluble extracts: recruitment of lymphocyte-target conjugates and killer cells and activation of programming for lysis

Echinacea purpurea, a plant originally used by native Americans to treat respiratory infections, has also been shown to exert immunomodulatory activities both in vivo and in vitro. However, the mechanism underlying Echinacea-induced immunomodulation remains largely unknown. This study examined in vitro the effects of soluble extracts of E. purpurea on natural killer (NK) cells present in human peripheral blood mononuclear cells (PBMC). Flow cytometric methods were used to examine activation, cytotoxicity, NK-target binding, and killer cell frequency. Treatment of PBMC with Echinacea overnight resulted in the activation of CD69 expression and increase in mean fluorescence intensity in both the CD16+ and CD16+CD56+ NK subsets. However, the frequency of CD16+ cells was decreased as well as the mean fluorescence intensity was down-regulated. NK cytotoxicity was augmented 100% at the concentration of 0.1 microg/ml of Echinacea in a short time (4-h) assay. Examination at the single cell level revealed augmentation of the frequency of CD56+ NK-target conjugates and a plateau was reached after 30-60 min of incubation. Likewise, the frequency of CD56+ killer cells in the conjugates was also significantly increased by Echinacea. There was recruitment of non-conjugated CD56+ cells into CD16+ NK-target conjugates and activation of the NK-target non-killer conjugates into killer cells. These findings demonstrate that Echinacea extracts are potent activators of NK cytotoxicity. Echinacea augments the frequency of NK target conjugates and activates the programming for lysis of NK cells.     

类风湿关节炎合并肺部感染患者外周血T淋巴细胞和NK细胞水平及其临床意义

目的探究类风湿关节炎(RA)合并肺部感染患者外周血T淋巴细胞和自然杀伤细胞(NK细胞)的水平及其临床意义。方法选取48例RA合并肺部感染患者作为RA合并感染组,64例RA未合并肺部感染患者作为RA未合并感染组,另选取同期于本院健康体检中心进行体检的30例健康成年人作为对照组。比较三组外周血T淋巴细胞亚群及NK细胞水平,比较稳定期与活动期RA合并与未合并肺部感染患者的T淋巴细胞亚群及NK细胞水平。结果RA合并感染组CD3⁺(641.21±438.08)个/μl、CD4⁺(171.58±96.42)个/μl、CD8⁺(215.48±110.16)个/μl、CD4⁺/CD8⁺(0.82±0.26)、NK细胞(26.57±4.88)个/μl;RA未合并感染组CD3⁺(1051.36±434.65)个/μl、CD4⁺(308.07±101.69)个/μl、CD8⁺(324.17±108.16)个/μl、CD4⁺/CD8⁺(0.96±0.24)、NK细胞(40.52±8.92)个/μl;对照组CD3⁺(1403.00±402.77)个/μl、CD4⁺(610.07±82.58)个/μl、CD8⁺(532.47±168.45)个/μl、CD4⁺/CD8⁺(1.35±0.21)、NK细胞(365.15±117.61)个/μl。RA合并感染组、RA未合并感染组CD3⁺、CD4⁺、CD8⁺、CD4⁺/CD8⁺、NK细胞水平均低于对照组,差异有统计学意义(P<0.05)。RA合并感染组CD3⁺、CD4⁺、CD8⁺、CD4⁺/CD8⁺、NK细胞水平均低于RA未合并感染组,差异有统计学意义(P<0.05)。稳定期RA合并肺部感染患者CD3⁺、CD4⁺、CD8⁺、CD4⁺/CD8⁺、NK细胞水平均低于稳定期RA未合并肺部感染患者,差异有统计学意义(P<0.05);活动期RA合并肺部感染患者CD3⁺、CD4⁺、CD8⁺、CD4⁺/CD8⁺、NK细胞水平均低于活动期RA未合并肺部感染患者,差异有统计学意义(P<0.05)。结论合并肺部感染的RA患者T淋巴细胞、NK细胞明显偏低,T淋巴细胞及NK细胞可能在一定程度上对RA合并肺部感染发挥一定的预测价值,指导临床诊疗。     

Cytokine and chemokine based control of HIV infection and replication

HIV infects and propagates into CD4+ T lymphocytes and macrophages, although many other cell types play an important role in virus spreading and pathogenesis. In addition to regulatory viral proteins, the cytokine network has early been implicated as a major controller of the plastic capacity of HIV to spread productively or rather remain silently integrated in the chromosomes of infected cells. The recent discovery of CCR5 and CXCR4 as essential entry co-receptors together with CD4 has highlighted a novel and potentially important step in the pharmacological hunt for more effective antiviral agents. In addition to regulate HIV expression and replication, several cytokines have demonstrated the capacity of up- or down-modulating chemokine receptors including CCR5 and CXCR4 with the consequence of influencing the susceptibility of T cells and macrophages to HIV infection. Pharmacological agents such as pertussis toxin B-oligomer have demonstrated HIV suppressive effects via non competitive binding of CCR5, whereas interferons or interleukin-16 (IL-16) can prevent post-entry steps in HIV expression. At the clinical level, several cytokines or their receptors are useful markers for monitoring disease progression and its consequence on the immune system. Cytokine-based therapy represents a realistic complementary approach to traditional antiretroviral therapy potentially capable of restoring important adaptive or innate immune functions ultimately curtailing HIV spreading and its consequences on the immune system, as exemplified by the experimental clinical use of IL-2.     

Immunosenescence in chronic HIV infected patients impairs essential functions of their natural killer cells

The HIV/AIDS pandemic still represents an important global health issue. There is no sterilizing cure, therefore a continuous treatment is necessary, which caused the emerged idea of HIV as a chronic inflammatory disease that may also affect healthy aging. Considering that the activation profile of some innate cells such as natural killer cells has previously been associated to HIV progression, it remains to be better defined this activation status of NK cells considering the time of HIV infection. In this study, we characterized NK cell phenotype and function during acute and chronic HIV infection and also investigated markers of immunosenescence in these cells. Our results showed that chronic infected patients remained with elevated levels of some plasma inflammatory molecules (IP-10, sCD14) and a concurrent expansion of the non-functional NK cell subset (CD3^-CD56^-CD16⁺). NK cells from the chronic infected group displayed an activated profile with higher levels of cytokines and chemokines production (TNF-α, IL-12, IFN-α2, IFN-γ, IL-6, RANTES, MCP-1, IL-10, IL-4 and IL-5). The production of these molecules was positively correlated to the time of infection. Moreover, we noted a possible association of higher global DNA methylation frequency of NK cells in two HIV patients in the advanced stage of disease. Chronic infected patients also showed a trend towards higher production of reactive oxygen species by their NK cells which altogether suggest the evolution of these cells to a senescent state that might be further evaluated.     

HIV-1-induced depletion of CD4+ T cells in the gut: mechanism and therapeutic implications

The mechanism of CD4+ T cell depletion remains a central unresolved issue in AIDS research. Recent studies have examined the massive depletion of CD4+ T cells observed in macaque models of acute HIV infection. A key question is whether the observed CD4+ T cell death is due to direct consequences of viral infection and to indirect mechanisms including increased expression of mediators of T-cell apoptosis. The therapeutic implications of the early CD4+ T cell loss are discussed.     

慢性乙型肝炎病毒感染对外周血单个核细胞中凋亡分子表达的影响及其与免疫功能的相关性

目的 研究慢性乙型肝炎病毒(HBV)感染对外周血单个核细胞中凋亡分子表达的影响及其与免疫功能的相关性.方法 选择76例慢性乙型肝炎(CHB)患者和体检的54例健康志愿者,分别作为CHB组和对照组,采集血清并测定凋亡分子含量、采集外周血单个核细胞并测定凋亡分子表达量以及免疫细胞含量.结果 CHB组患者血清中凋亡分子Fas、FasL、Caspase-3、Caspase-6、Caspase-8的含量以及外周血单个核细胞中Fas、FasL、Caspase-3、Caspase-6、Caspase-8的mRNA含量均显著高于对照组;CHB组患者外周血中CD3+ CD4+T细胞、CD3+ CD8+T细胞、CD16+ CD56+ NK细胞的百分比及CD4+/CD8+的比例均显著低于对照组;外周血单个核细胞中Fas、FasL、Caspase-3、Caspase-6、Caspase-8的mRNA含量与CD3+ CD4+T细胞、CD3 +CD8+T细胞、CD16+ CD56+自然杀伤(NK)细胞的百分比呈负相关.结论 慢性HBV感染能够增加外周血单个核细胞中凋亡分子的表达,进而造成T淋巴细胞和NK细胞凋亡、抑制细胞免疫应答和非特异性免疫应.     

类风湿关节炎患者外周血B淋巴细胞及自然杀伤细胞与临床相关性分析

目的 探讨类风湿关节炎(RA)患者外周血B淋巴细胞及自然杀伤(NK)细胞的变化情况,了解其变化在类风湿关节炎发病及炎症活动中的意义.方法 采用流式细胞仪荧光抗体标记法分别对197例类风湿关节炎患者的外周血淋巴细胞进行CD3/CD8/CD45/CD4及CD3/CD16 CD56/CD45/CD19四色荧光抗体(B.D)标记,分析比较类风湿关节炎患者外周血淋巴细胞比例情况,并与类风湿关节炎疾病活动性评分(DAS28)、压痛关节数、肿胀关节数、晨僵时间、医生和患者对疾病活动性的整体评价(VAS)、血红细胞沉降率、C反应蛋白及血清学抗体(AKA,APF,RF,CCP)及是否合并感染等并发症进行相关分析.结果 类风湿关节炎组外周血淋巴细胞中CD3-CD19+细胞和CD3-CD16+CD56细胞占总淋巴细胞数的百分率分别为(12.09±3.47)%和(15.02±2.56)%;类风湿关节炎患者外周血CD3-CD19+细胞和CD3-CD16+CD56+细胞与DAS28呈明显正相关(P<0.05);CD3-CD19+细胞数值与血清抗环瓜氨酸肽抗体水平呈正相关(P<0.05);比较出现感染的患者其免疫功能与未发生感染的患者之间CD3-CD19+细胞数值,CD3-CD16+CD56+细胞数值差异有统计学意义(P<0.05);比较出现肺间质病变的患者其免疫功能与未发生肺间质病变的患者之间CD3-CD19+细胞数值差异有统计学意义(P<0.05);比较合并干燥综合征的患者CD3-CD19-+细胞数值、CD3-CD16+CD56+细胞数值与未发生干燥综合征的患者差异无统计学意义(P>0.05).结论 类风湿关节炎患者外周血淋巴细胞存在比例失衡,CD3-CD19+细胞和CD3-CD16+CD56+细胞数量的异常可能是类风湿关节炎发病、炎症活动及合并感染的重要影响因素.

Abstract：

Objective To explore B cells and natural killer(NK)cells changes in pefipheral blood of rheumatoid arthritis(RA)patients to understand the role of the changes in RA patients and inflammation activities of disease.Methods All the RA patients selected into this study were divided into different disease activity group according to Disease Activity Score(DAS28).The peripheral blood mononuclear cells were cultured in vitro.The lymphocytes were marked by four-color fluorescent antibody of CD3/CD4/CD8/CD19 and CD16/CD3/CD19/CD56,and then detected lymphocyte by flow cytometry.We markered and detected the number of the T phenotype cells,B phenotype cells,NK phenotype cells.The correlation between the lymphocyte and diseases activity score,tenderness joint swelling of the joints number,morning stiffness time,doctors and patients to disease activity glogal assessment(VAS),red blood cell subsidence ratio,C.reactive protein and serological antibody was analyzed.Results The proportions of the CD3-CD19+cell and the CD3-CD16+CD56+cell in peripheral iymphocytes was(12.09±3.47)%and(15.02±2.56)%respectively in RA group.Correlation analysis indicated significant negative correlations of the proportions of CD3-CD19+cells with DAS28-4 and a-ccp(P<0.05).Furthermore,CD3+CD19-and CD1-CD19+ cells still showed significant correlation between with pSS and ILD and without(P<0.05).Conclusion There is an imbalance in the proportions of the CD3-CD19+cell and the CD3-CD16+CD56+cell in peripheral iymphocytes with RA.The abnormality of iymphocytes may be a coincidence in the inflammation and infection in patients with RA.     

Effect of azithromycin on natural killer cell function

Azithromycin (AZM), a macrolide antibiotic for treating mycoplasma infections, may exhibit anti-inflammatory activity aside from its antimicrobial effect, providing additional therapeutic benefit. Natural killer (NK) cells, a first-line innate immune defense against microbial invasions, paradoxically exert a detrimental effect in protecting mycoplasma infection. Little was known regarding the effect of AZM on NK cells. In the present study, we investigated the ability of azithromycin to influence natural killer (NK) cell function with regard to activation, apoptosis and cytotoxic function. AZM had little effect on NK receptor expression and cytotoxic function of NK-92 cells. However, AZM did show a dose-dependent suppression on IL-15-induced CD69 expression of primary NK cells. AZM inhibited the cytotoxicity against K562 cells of resting and IL-15 activated primary NK cells possibly through down-regulation of perforin expression, especially on CD16(+)CD56(+) NK subsets. AZM exerted a dose-dependent inhibition of IFN-gamma and TNF-alpha production from NK-92 cells, but did not affect the cytokine production of IL-15 activated primary NK cells. Taken together, AZM down-regulates NK cytotoxicity and cytokine production and may provide therapeutic benefits aside from its antimicrobial activity.     

Higher levels of HIV DNA in memory and naive CD4(+) T cell subsets of viremic compared to non-viremic patients after 18 and 24 months of HAART

The degree of infection of memory and naive CD4⁺ T cells in patients treated with HAART and with durable undetectable or detectable viral load in plasma was evaluated. The following two groups of patients were analyzed cross-sectionally: (i) patients with undetectable HIV RNA plasma levels during follow-up (responders); (ii) patients with no reduction or with rebound in HIV RNA levels during treatment (non-responders). Patients were examined following 6, 12, 18 and 24 months of HAART, respectively, by quantifying: (i) plasma HIV RNA load; (ii) CD4⁺ T cells; (iii) memory and naive CD4⁺ T cells; (iv) HIV DNA levels in memory and naive CD4⁺ T cells. HIV RNA plasma levels were significantly higher in non-responders vs responders at each time point (P<0.02), while CD4⁺ T cell counts as well as memory and naive CD4⁺ T cell levels were comparable in both viremic and non-viremic patients. However, higher HIV DNA values were observed in both memory and naive CD4⁺ T cells of non-responders vs responders after 18 and 24 months of HAART (P<0.02), suggesting an increased amount of HIV-infected naive CD4⁺ T cells and a sustained high degree of infection of memory CD4⁺ T cells. Immunological reconstitution following HAART might potentially be hampered in viremic patients despite the absolute increase in CD4⁺ T cell counts.     

HLA-E siRNA沉默肝癌细胞HLA-E基因的表达

目的针对HLA-EmRNA靶序列不同位点,设计合成多个siRNA链,定量分析其对HLA-E(+)肝癌BEL-7402细胞的基因沉默效率,筛选最佳抑制效果的siRNA。方法用IFN-γ(5×105IU·L-1)诱导BEL-7402细胞表达HLA-E基因,经流式细胞技术纯化后作为靶细胞。设计并合成3条HLA-E siRNA链(A、B、C),将各siRNA(0.1mmol·L-1)经脂质体Lipofectamin 2000转染至靶细胞。采用细胞免疫荧光、流式细胞技术、Western杂交、实时PCR等定量方法,比较48h后各siRNA的基因沉默效果,并观察HLA-E基因沉默对NK肿瘤细胞杀伤的影响。结果与空白对照、非特异组相比,3组(A、B、C组)HLA-E siRNA均明显抑制细胞HLA-E抗原、蛋白产物、mRNA、细胞表面HLA-E分子的表达(P<0.01),B、C组抑制效果接近90%,高于A组(P<0.01)。A、B、C组NK肿瘤杀伤率升高(P<0.01),而B、C组肿瘤杀伤效果高于A组(P<0.01)。结论经筛选的HLA-EsiRNA能特异、高效沉默肝癌细胞HLA-E基因表达,可能抑制其非经典HLA-Ⅰ途径免疫逃避,为肝癌"基因-免疫"治疗提供新的治疗策略。     

Cell cycle dysregulation during HIV infection: perspectives of a target based therapy

Human immunodeficiency virus (HIV) infection is characterized by a severe depletion of both CD4+ and CD8+ T cells, representing the result of virus-mediated killing of infected lymphocytes and the programmed cell death (apoptosis) of the uninfected bystander cells. Since only a small fraction of T lymphocytes are depleted by viral killing, apoptosis represents one of the most important mechanism of T cell death during HIV infection. Several apoptotic pathways can be triggered by the different stimuli: persistent T lymphocyte activation; altered death receptor (Fas, TNF-R, TRAIL R1-R2) membrane expression; viral proteins as well as gp120, Tat, and Nef; host factors such as the unbalance of cytokine synthesis by lymphocyte. Nevertheless, new evidences have demonstrated that the persistent HIV induced T cell activation and proliferation cause a cell cycle dysregulation resulting in a 5-fold increase in apoptotic cells. This perturbation represents a link between HIV infection, T cell activation, accelerated cell turnover and increased apoptosis and may thus represent a new therapeutic target. In fact, Interleukin-2 administration reverts such a cell cycle dysregulation and reduces activation induced T cell apoptosis. Herein we analyze the main HIV-related mechanisms of host cell death, that are dysregulation of the cell cycle and apoptosis induction of T lymphocytes. Finally, the role of cytokines at the site of infection and their association with apoptosis will be discussed to get insights into the immunological perturbations accounting for an accelerated disease progression. Current therapeutic approaches and strategies, like HAART and recombinant cytokines, that may, successfully, improve the immune-system dysregulation, are also discussed.     

Mice Chronically Infected with Chimeric HIV Resist Peripheral and Brain Superinfection: A Model of Protective Immunity to HIV

Infection by some viruses induces immunity to reinfection, providing a means to identify protective epitopes. To investigate resistance to reinfection in an animal model of HIV disease and its control, we employed infection of mice with chimeric HIV, EcoHIV. When immunocompetent mice were infected by intraperitoneal (IP) injection of EcoHIV, they resisted subsequent secondary infection by IP injection, consistent with a systemic antiviral immune response. To investigate the potential role of these responses in restricting neurotropic HIV infection, we established a protocol for efficient EcoHIV expression in the brain following intracranial (IC) inoculation of virus. When mice were inoculated by IP injection and secondarily by IC injection, they also controlled EcoHIV replication in the brain. To investigate their role in EcoHIV antiviral responses, CD8+ T lymphocytes were isolated from spleens of EcoHIV infected and uninfected mice and adoptively transferred to isogenic recipients. Recipients of EcoHIV primed CD8+ cells resisted subsequent EcoHIV infection compared to recipients of cells from uninfected donors. CD8+ spleen cells from EcoHIV-infected mice also mounted modest but significant interferon-γ responses to two HIV Gag peptide pools. These findings suggest EcoHIV-infected mice may serve as a useful system to investigate the induction of anti-HIV protective immunity for eventual translation to human beings.     

HIV病毒阳性患者合并口腔病损与CD_4~＋ T淋巴细胞免疫识别的相关性

目的分析HIV阳性合并各种口腔病损患者CD4＋T细胞免疫识别的变化趋势,探讨识别特征性细胞因子对于认识AIDS的发生发展规律及控制口腔表征的临床治疗具有重要意义。方法现将作者在埃塞俄比亚首都亚的斯亚贝巴大学口腔医学中心收住的32例HIV感染伴口腔黏膜损害患者入选本项临床观测;在入院后1周内及治疗过程中反复采集外周血,经流式细胞仪进行CD4＋T细胞检测计数,SPSS13.0软件包统计分析。结果 32例HIV感染伴口腔黏膜损害患者均有不同程度CD4＋T淋巴细胞数量下降,CD4＋T淋巴细胞数与出现口腔黏膜病损成反比,即CD4＋T淋巴细胞数值越小,合并口腔黏膜病损的破坏程度越明显。结论 HIV阳性患者中CD4＋T淋巴细胞数与口腔黏膜病损程度呈明显的负相关关系。