Alterations of Natural Killer Cell and T-Lymphocyte Counts in Adults Infected with Human Immunodeficiency Virus through Blood and Plasma Sold in the Past in China and in Whom Infection Has Progressed Slowly over a Long Period

Natural killer (NK) cells, natural killer T (NKT) cells, and T lymphocytes were analyzed by using a flow cytometer in 225 human immunodeficiency virus (HIV)-positive individuals infected through the past sale of blood and plasma without receiving antiretroviral therapy in the People’s Republic of China. According to CD4 T-cell counts these HIV-infected adults were stratified into three groups: long-term slow progressors, HIV-infected subjects, and AIDS patients. NK cell counts in long-term slow progressors were higher compared to HIV infection and AIDS patients (P < 0.05) and lower compared to normal controls (P < 0.05), whereas NKT cell counts in slow progressors and the HIV infection group were not different from those of normal controls. NK cell counts in HIV-seropositive subjects were positively correlated with CD4 T-cell counts (P < 0.05), and NKT cell counts were positively correlated with CD4 T-cell and CD8 T-cell counts (P < 0.05). The CD8 T-cell counts were higher in slow progressors compared to those with HIV infection, AIDS patients, and normal controls. These results indicated that HIV infection causes alterations of NK cells and T cells in slow progressors, HIV-infected subjects, and AIDS patient groups, but no difference was found in NKT cell counts and percentages in slow progressors and the HIV-infected group compared to normal controls.     

HIV感染症状长期不进展者NK细胞变化研究

目的探讨HIV长期不进展者NK细胞的变化. 方法应用流式细胞术对HIV长期不进展者、典型进展者和HIV-抗体阴性正常对照外周血NK细胞、NKT细胞及NK细胞趋化因子受体等进行研究. 结果长期不进展者NKT细胞绝对计数与正常对照差异无统计学意义(P＝0.301),高于HIV感染者和艾滋病病人(P＝0.01, P＝0.002);长期不进展者NK细胞绝对计数低于正常对照(P＝0.03),高于HIV感染者和艾滋病病人(P＝0.005, P＜0.0001);长期不进展者NK细胞与CD4+ T淋巴细胞呈正相关(r＝0.393,P＝0.001);NKT细胞与CD8+ T淋巴细胞呈正相关(r＝0.372,P＝0.002).长期不进展者NK细胞表达的CCR5受体低于典型进展者和正常对照(P＜0.01). 结论 NK细胞的变化与HIV疾病进展相关,值得深入研究.     

中国HIV/AIDS患者NK细胞及NKT细胞变化的检测

目的　探讨HIV感染后机体NK(naturalkillercells)及NKT细胞的变化情况。方法　取外周血细胞 ,用标记荧光的抗体进行染色 ,流式细胞仪分析HIV AIDS患者NK和NKT细胞的变化。结果　HIV AIDS患者NK、NKT细胞和CD4 + T细胞显著低于正常对照 ;CD8+ T细胞显著高于正常对照。HIV AIDS患者NK百分数显著低于正常对照 ,与CD4 + T细胞数量成正比 ,r=0 .2 89,P <0 .0 1 ;NKT细胞数量与CD4 + T细胞数量成正比 ,r =0 .378,P <0 .0 1 ;与CD8+ T细胞数量成正比 ,r =0 .340 ,P <0 .0 1 ;长期不进展组NKT、NK细胞数量与正常对照组差异无显著性。结论　HIV感染可明显降低HIV AIDS患者NK和NKT细胞数量 ,NK和NKT细胞变化与疾病进展密切相关。     

Effect of splenectomy on T-cell subsets and plasma HIV viral titers in HIV-infected patients

OBJECTIVE: In previous studies we have shown that removal of the spleen in HIV-infected people during the asymptomatic phase of disease results in slower time to AIDS and may also result in improved survival. In this paper, we examine whether splenectomy affects lymphocyte counts, T-cell subsets, and HIV plasma viremia in a manner that could explain the clinical benefits associated with this intervention. METHODS: 10 HIV-infected patients who underwent splenectomy and 23 HIV-infected controls with idiopathic thrombocytopenia purpura who did not undergo splenectomy were studied. These groups were compared for changes in cell subpopulations and HIV plasma viremia. RESULTS: Splenectomy resulted in increases in absolute lymphocyte numbers with rises in both CD4 and CD8 counts, whereas CD4 and CD8 percentage levels remained unchanged. In controls, absolute and percentage CD4+ T-cell counts declined with time from date of HIV infection. Plasma viremia decreased more than threefold, the limit of biologic variation, after splenectomy in 4 of 9 subjects and in only 1 of 18 controls. The proportion of subjects exhibiting reduced viremia following splenectomy was greater than that in HIV-infected patients that did not undergo splenectomy (chi 2 test, P = .015). CONCLUSIONS: Improved survival and time to AIDS in splenectomized HIV-infected patients is associated with temporary reduction of plasma viremia and increase in absolute CD4 and CD8 counts. These effects could not be attributed to antiretroviral therapy because subjects were either untreated or treated with antiretroviral monotherapy during the observation period. These observations may have importance in the understanding of T-cell dynamics and the potential for splenectomy as an HIV reservoir-debulking procedure.     

Modulation of expression of the MHC class I-binding natural killer cell receptors, and NK activity in relation to viral load in HIV-infected/AIDS patients

The natural killer (NK) cells play an important role in viral infections via their spontaneous cytolytic activity against virus-infected cells as well as via secreting a variety of soluble mediators. The MHC class I-binding NK receptors of these cells have emerged as the most important regulators of the effector activities of cytolytic cells (both NK and CTL). We have studied the modulation of NK activity and the expression of NK receptors in HIV-infected/AIDS patients and report here that the NK activities of the patients with the lowest plasma HIV load were minimal and vice versa, suggesting a decrease in this activity following suppression of HIV replication. Interestingly, the NK activity correlated negatively with the peripheral blood CD4+ T-cell counts of these patients. Furthermore, these patients showed decreased percentages of CD56+ cells expressing NK receptors of the immunoglobulin superfamily, whereas the percentages of CD8+ cells expressing these receptors were increased. Moreover, the expression of C-type lectin-like NK receptor-associated invariant molecule CD94 was increased on CD8+ cells in these patients as compared with HIV-seronegative controls. These changes in the expression of NK receptors were also evident within groups of these patients having different viral loads. These results show, for the first time, decreased innate immunity and changes in the expression of NK receptors on cytolytic cells in relation to viral burden in HIV-infected/AIDS patient.     

抗病毒治疗后HIV 感染者NKT 样细胞衰老和体外增殖研究

目的:研究高效抗逆转录病毒治疗(Highly active antiretroviral therapy,HAART)后NKT 样细胞衰老和体外增殖情况。方法:选取未接受HAART 治疗、接受HAART 治疗的HIV 感染者以及健康人的外周血细胞,利用流式细胞仪检测接受HAARRT 治疗前后的HIV 感染者NKT 样细胞CD57 的表达情况以及体外增殖能力。结果:HIV 感染者在HAART 治疗前NKT 样细胞的百分数显著低于健康对照组(P<0.01),HAART 治疗后恢复(P<0.05);HAART 治疗前NKT 样细胞CD57 的表达明显高于健康对照组(P<0.01),HAART 治疗后恢复(P<0.05);HAART 治疗前NKT 样细胞体外增殖能力明显低于健康对照组,HAART 治疗后有所恢复。结论:经过HAART 治疗后,HIV 感染者NKT 样细胞的数量、CD57 表达以及体外增殖能力有所恢复。     

Deficient Antibody-Dependent Cellular Cytotoxicity against Human Immunodeficiency Virus (HIV)-Expressing Target Cells in Perinatal HIV Infection

Peripheral blood mononuclear cells (PBMC) of human immunodeficiency virus (HIV)-infected children, age-matched HIV-seronegative controls, and HIV-infected asymptomatic and symptomatic adults were compared for their ability to mediate antibody-dependent cellular cytotoxicity (ADCC) and natural killer (NK) cell-mediated cytotoxicity against target cells expressing HIV or herpes simplex virus (HSV) antigens. Target cells consisted of CD4 lymphocytes purified from PBMC of HIV-seronegative adults and incubated with the IIIB strain of HIV, HUT78 cells chronically infected with IIIB, and HSV-infected human fibroblasts. PBMC of asymptomatic HIV-infected adults were generally able to lyse CD4 cells expressing HIV antigens. Direct correlation was found between the magnitude of lysis and absolute CD4 cell counts in these individuals. In contrast to these results, PBMC from HIV-infected children were generally unable to lyse IIIB-expressing CD4 cells, regardless of the children’s clinical status, age, or absolute CD4 cell counts. Cells from HIV-seronegative adults and children did not directly lyse these target cells either but, in contrast to cells of HIV-seropositive children, were able to mediate cell lysis when serum from an HIV-seropositive adult was added. However, effector cells from these HIV-infected children were able to mediate both ADCC against HSV-infected fibroblasts and NK cell-mediated cytotoxicity against IIIB-infected HUT78 cells. Reduced ability of PBMC from vertically HIV-infected children to mediate ADCC against HIV antigen-expressing CD4 cells may contribute to rapid progression to AIDS.     

Higher NK Cell IFN-γ Production is Associated with Delayed HIV Disease Progression in LTNPs

Natural killer (NK) cells are important effectors of the innate immune system that help control viral infections and tumorigenesis. However, the relationship between NK cell function and HIV disease progression remains poorly defined. In this study, we examined the function of NK cells in Chinese patients who were HIV-infected but treatment-naïve. These individuals include primary HIV-infected patients (PHIs), typical progressors (TPs), and long-term nonprogressors (LTNPs). We observed an increase of CD56^dim NK cells in PHIs, but the production of interferon-gamma (IFN-γ) and CD107a expression in PHIs were not altered compared with normal control subjects (NCs). However, the NK cells from LTNPs exhibited increased activities in IFN-γ production, CD107a expression and granzyme B change after K562 stimulation compared with NCs. Furthermore, the percentage of IFN-γ⁺CD107a^? NK cells in LTNPs was higher than that in TPs, PHIs and NCs; levels of IFN-γ production in LTNP NK cells exhibited an inverse correlation with viral loads. Similar correlations, however, were not observed in the PHI and TP groups. Taken together, these data demonstrate that enhanced NK cell function may contribute to the control of HIV infection, and increased IFN-γ secretion may be associated with delayed disease progression.     

Inverse relationship of CD8+CD11+ suppressor T cells with human immunodeficiency virus (HIV)-specific cellular cytotoxicity and natural killer cell activity in HIV infection.

Profiles of CD8+CD11+ T suppressor cells, human immunodeficiency virus (HIV)-env-specific cytotoxic T-lymphocyte (CTL) activities, and natural killer (NK) cell activity were studied in 12 asymptomatic untreated HIV-infected patients. These patients were followed for 4-7 months. NK activity, HIV-env-specific CTL activities mediated by CD4+, CD8+ T cells and CD8+CD11+ T-suppressor cell number remained stable in seven patients during the study period. Alternatively, NK and HIV-specific CTL activities decreased and CD8+CD11+ cell number increased in five patients whose CD4+ T-cell number fell, and in four of these five patients serum p24 antigen level increased, and they developed minor clinical signs of disease progression during the study period. CD8+CD11+ cells are present in higher percentage (10-45% of peripheral blood mononuclear cells) in these HIV-infected patients as compared to those in normal individuals (3-5%). Our results suggest that CD8+CD11+ cells, NK, and HIV-specific cytotoxic activities may be helpful in monitoring prognosis of HIV infection. These observations also suggest that CD8+CD11+ cells may play an important role in the failure of host immune defences against HIV.     

慢性HIV/AIDS患者T淋巴细胞凋亡与疾病进展关系的研究

目的 探讨慢性未经抗病毒治疗的HIV/AIDS患者T淋巴细胞及各亚群凋亡与疾病进展的相关性.方法 以36例慢性未经抗病毒治疗的HIV/AIDS患者为研究对象,根据CD4细胞计数分为3组:<200个/μl组,200～350个/μl组,>350个/μl组,同时选取16例健康志愿者作对照,分离外周血单核细胞(PBMC)后,采用CD45RO及CD27标记T细胞亚群,Annexin V标记细胞凋亡,用流式细胞仪检测各项指标.其中4例患者及4例健康志愿者的PBMC在体外培养,比较分析体外培养0、3、6、12、24 h不同时间点T细胞凋亡的变化情况.结果 (1)HIV/AIDS患者CD4~+、CD8~+T细胞及各亚群上Annexin V表达百分比均显著高于健康人(P<0.05),但3组患者之间比较差异无统计学意义(P>0.05);(2)HIV/AIDS患者CD4~+、CD8~+T细胞及各业群上Annexin V表达百分比与CD4~+T细胞计数及病毒载显均无显著相关性(P>0.05);(3)随着体外细胞培养时间的延长,HIV/AIDS患者CD4~+T细胞的凋亡及死亡细胞百分比均显著高于健康人(P<0.05),并且HIV/AIDS患者CD4~+T细胞较CD8~+T细胞更易发生凋亡和死亡.结论 HIV/AIDS患者的T细胞凋亡水平显著高于健康人,并且CD4~+T细胞较CD8~+T细胞更易发生凋亡和死亡,但是T细胞凋亡水平与HIV的疾病进展程度并没有相关性.     

CD1d-restricted natural killer T cells are potent targets for human immunodeficiency virus infection

Invariant human natural killer T cells (NKT) express a restricted T-cell receptor (TCR) Valpha24Vbeta11 repertoire. These cells share both phenotypic and functional similarities between NK and T cells. Given the emerging role of NKT cells as critical cells in bridging the gap between innate and adaptive immunity, we examined their susceptibility to productive human immunodeficiency virus (HIV) infection by T-tropic, M-tropic, and primary isolates of HIV. We generated three human NKT cell clones (CA5, CA29, and CA31). Phenotypic characterization of these Valpha24+ Vbeta11+ clones indicated that they were predominately positive for CD4, CD161, HLA-DR, CD38, CD45RO, and CD95 expression. The NKT cell clones expressed significantly more surface CCR5 molecules/cell and lower CXCR4 molecules/cell than phytohaemagglutinin-stimulated peripheral blood mononuclear cells (PBMC). Consistent with the surface expression of CCR5 and CXCR4, the NKT clones were also selectively susceptible to HIV M-tropic, T-tropic, and primary isolate infection, as evaluated by both HIV p24 enzyme-linked immunosorbent assay and intracellular staining of HIV proteins. The amount of p24 production was dependent on the NKT clone studied and the HIV strain used. Clones CA29 and CA31 were also susceptible to HIV IIIB infection. The virions produced by these clones were able to productively infect PHA-stimulated PBMCs with the same kinetics as for primary infection of CD4+ blast. Collectively, this data demonstrates that NKT cells can be a target for productive HIV infection but with a lag in the time to peak p24 production.     

Changes in NK and NKT cells in mesenteric lymph nodes after a Schistosoma japonicum infection

The mesenteric lymph node (MLN) is the main draining lymph node in mouse enterocoelia, which contains many types of immune cells. Among these cells, natural killer (NK) and natural killer T (NKT) cells belong to innate lymphoid cells (ILCs), which have potent activities for controlling a variety of pathogenic infections. In this study, C57BL/6 mice were infected with Schistosoma japonicum for 5–7 weeks. Lymphocytes were isolated from the MLN to detect changes in the phenotype and function of NK and NKT cells using a fluorescence activating cell sorter (FACS). These results demonstrated that a S. japonicum infection could significantly increase the percentage of NK cells in the mouse MLN, (P?<?0.05). We found an increase in the cell number of both NK and NKT cells. In addition, we found that NK and NKT cells from infected mice expressed higher levels of CD69 compared to normal mice (P?<?0.05). These results demonstrated that a S. japonicum infection could induce MLN NK and NKT cell activation. Moreover, we found that the expression of CD4 was increased in infected MLN NK cells (P?<?0.05). Furthermore, intracellular cytokine staining revealed that expression of IL-4 and IL-17 were significantly enhanced in both the NK and NKT cells of infected mice after phorbol 12-myristate 13-acetate (PMA) and ionomycin stimulation (P?<?0.05). Taken together, these results indicated that infection-induced MLN NK and NKT cells might play roles in modulating the classical T cell response. Finally, our results indicated that the expression of CD94 was decreased in NK cells, suggesting that the downregulation of CD94 expression might served as a mechanism in NK cell activation.     

未治疗HIV 感染者NKT 样细胞活化、凋亡和增殖的相关研究

目的:研究HIV 感染后NKT 样细胞活化、凋亡和增殖的变化情况。方法:选取47 名未治疗的HIV 感染者和31 名健康对照者,提取外周血细胞,用荧光标记抗体进行染色,利用流式细胞仪检测HIV 感染者NKT 样细胞HLA-DR、Annexin-V、Ki-67 等表面分子的表达。结果:未治疗HIV 感染者NKT 样细胞百分数为(3.03±1.61)%,正常人NKT 样细胞百分数为(8.30±7.42)%,HIV 感染者NKT 样细胞百分数显著低于健康对照组(P<0.05);未治疗HIV 感染者HLA-DR 表达为(5.40±4.10)%,健康对照组HLA-DR 表达为(0.89±0.83)%,HIV 感染者活化程度明显高于健康对照组(P<0.001),且活化程度与CD4+ T 细胞计数呈负相关(r =-0.885 7,P<0.05);未治疗HIV 感染者Annexin-V 表达为(30.21±13.15)%,凋亡程度明显高于健康对照组(5.40±8.05)%,(P<0.01);未治疗HIV 感染者Ki-67 的表达为(11.15±4.76)%,增殖能力明显低于健康对照组(27.63±18.31)%,(P<0.05)。结论:HIV 感染可明显降低NKT 样细胞数量及增殖能力,而其活化及凋亡能力增加。     

HIV 感染者调节性T 细胞表面B、T 淋巴细胞衰减因子的表达研究

目的:对HIV 感染者调节性T 细胞(Regulatory T cell,Treg)上B 、T 淋巴细胞衰减因子(B and T lymphocyte at-tenuator,BTLA)的表达水平进行检测,并探讨其在HIV 感染进程中的作用。方法:选取24 例感染在一年之内的HIV 早期感染者(Early HIV infected patients,EHI 组)、14 例感染超过一年的HIV 慢性感染者(CD4+ T 计数>200 cells/ μl,HIV 组)、6 例AIDS患者(CD4+ T 计数<200 cells/ μl,AIDS 组)和9 例健康人作为对照,应用流式细胞仪检测不同时期感染者及健康对照者Treg 细胞BTLA 的表达水平,分析其与疾病进展及免疫活化的相关性。结果:随着HIV 疾病进展,EHI 组、HIV 组及AIDS 组Treg 细胞BTLA 表达水平依次升高,其中HIV 组与AIDS 组Treg 细胞BTLA 表达水平显著高于EHI 组(P<0.05 及P<0.01),AIDS 组Treg 细胞BTLA 的表达水平高于健康对照(P<0.05);Treg 细胞BTLA 表达水平与CD4+ T 淋巴细胞计数呈负相关(P<0.001),与病毒载量呈正相关(P<0.01);Treg 细胞BTLA 表达水平与活化CD4+ CD38+ T 淋巴细胞及CD4+ HLA-DR+ T 淋巴细胞呈正相关(P<0.001,P<0.001)。结论:HIV 感染者Treg 细胞BTLA 表达升高,与疾病进展显著相关,提示其可能通过加强Treg 细胞的抑制功能加速疾病进展,并为未来HIV 感染的干预提供信息。     

Expression of human CD226 on T cells and natural killer cells and of soluble CD226 in plasma of HIV-1-infected Chinese patients

Our objective was to detect the expression of CD226 on natural killer (NK) cells and T cells, and to measure the amount of soluble CD226 in the plasma of HIV-infected individuals, in order to evaluate the function of CD226 in HIV infection. Thirty-four untreated HIV-1-infected patients and 26 normal controls were enrolled and three-color flow cytometry was used to detect the expression of CD226 on T lymphocytes and NK cells in whole blood samples taken from the patients and normal controls, and in HIV-1SF33-infected peripheral blood mononuclear cells (PBMCs). An enzymelinked immunosorbent assay (ELISA) was used to detect the level of soluble CD226 in the plasma of HIV-infected patients and normal controls and in the supernatant of HIV-1SF33-infected cells. The level of CD226 expression on CD3+, CD4+, and CD8+ T cells and on CD3- CD16+ NK cells of HIV-infected patients was significantly higher than that of normal controls (p < 0.01). The level of soluble CD226 in the plasma of HIV-infected patients was also significantly higher than that of normal controls (p < 0.01). After stimulation with HIV-1SF33, the level of CD226 expression on CD3+ T cells and CD3- CD16+ NK cells of cultured PBMCs reached peak values at 48 h, which was earlier than in uninfected control cells (72 h). The level of soluble CD226 in the supernatant of HIV- 1SF33-infected cell culture was higher than that of uninfected cells, and the level of soluble CD226 in the supernatant of HIV-1SF33-infected cells reached the peak value at 72 h, which was earlier than in uninfected control cells (96 h) but later than the time of peak CD226 expression on CD3+ T lymphocytes (48 h). We conclude that CD226 may be involved in the immune response to HIV infection and that further experiments are needed to find the function of CD226 in the pathogenesis of HIV infection.     

HIV/AIDS患者外周血B细胞数量以及TLR9 mRNA表达水平的研究

目的 探讨HIV-1感染后外周血B细胞数量的变化,以及B细胞TLR9 mRNA表达水平与HIV-1感染疾病进展的关系.方法 采集HIV/AIDS患者EDTA抗凝静脉血,荧光抗体染色后用流式细胞仪检测HIV/AIDS患者B细胞数量.密度梯度离心法分离外周血单个核细胞,应用MACS磁珠分选系统分选CD19+B细胞,并采用荧光定量实时PCR技术检测B细胞TLR9 mRNA水平.结果 HIV/AIDS患者B细胞数量显著低于健康对照组(P＜0.01),与CD4+T细胞数量呈正相关(r=0.534,P=0.006).HIV/AIDS患者外周血B细胞TIR9 mRNA的表达明显低于健康对照组(P=0.023),与CD4+T细胞数量呈正相关(r=0.390,P=0.040).结论 HIV感染可降低HIV/AIDS患者外周血B细胞数量以及B细胞TLR9 mRNA的表达量,B细胞数量和B细胞TLR9 mRNA的表达量均可能与疾病进展相关.     

Function of NKT cells, potential anti-HIV effector cells, are improved by beginning HAART during acute HIV-1 infection

NKT cells are a subset of lymphocytes that share features of T cells and NK cells and bridge the innate and adaptive immune responses. They are able to be infected by HIV, but their function in HIV-infected individuals is not known. NKT cell percentage and function was measured in individuals with acute HIV infection before and 1 year into highly active anti-retroviral therapy (HAART). This study demonstrates that percentages of both CD161+ NKT cells and CD161+, CD4+ NKT cells decline within the first few months after HIV-1 infection, but initiating therapy during the acute infection period can prevent a further decline in these NKT cell subsets during the first year. NKT cell function is also impaired during early HIV infection, but significantly improved by effective treatment with HAART. Finally, preservation of NKT cell function may be important in HIV-infected individuals, as NKT cells display an anti-HIV-1 activity in vitro, mediated by IFN-gamma secretion.     

HIV感染者NKT样细胞基线功能对疾病进程的影响

目的本实验通过检测HIV感染者NKT样细胞基线功能的变化,研究NKT样细胞对HIV感染疾病进程的影响。方法应用流式细胞术直接对HIV感染者以及健康对照外周血NKT样细胞IFN-γ分泌和CD107a表达进行研究。结果 NKT样细胞分泌IFN-γ百分比高者HIV疾病进展慢(P<0.008,P<0.001),与CD4+T细胞计数呈显著正相关(r=0.402,P=0.027),而与病毒载量呈显著负相关(r=-0.472,P=0.037)。结论 NKT样细胞功能较强,具有免疫保护作用,是延缓HIV病程的重要因素之一,可作为监测HIV疾病进展的指标。     

Enhancement of natural killer cell activity in human immunodeficiency virus-infected subjects by in vitro treatment with biologic response modifier OK-432.

A decrease in natural killer (NK) cell function has been related to the progression of human immunodeficiency virus (HIV) infection. In the present study, we assessed the ability of a streptococcus-derived biologic response modifier, OK-432, to augment NK lysis of uninfected K562 and U937 cells and HIV-infected U937 cells by peripheral blood mononuclear cells (PBMC) from HIV-seropositive homosexual men. Optimal two- to fourfold increases in lysis of the three targets were observed after pretreatment of PBMC from HIV-negative subjects for 4 h with 2 micrograms of OK-432 per ml. This effect was related primarily to gamma interferon (IFN-gamma) production induced by OK-432 and was not linked to production of tumor necrosis factors alpha and beta or to monocytes in the cultures. The enhancing effect of OK-432 on NK cell function was diminished but still evident in PBMC from subjects with relatively early-phase (< 3-year) HIV infection and high CD4+ cell counts and was lower in subjects with longer-term HIV infection (> 3 years), in association with reduced production of IFN-gamma. Augmentation of NK cell activity in HIV-infected men by OK-432 was comparable to that induced by treatment of cells with 1,000 U of IFN-alpha or interleukin 2 per ml. The data suggest that the NK cell-enhancing effects of OK-432 are at least in part mediated by IFN-gamma and that OK-432 may be effective in treatment of patients with early-phase HIV infection.     

Progression to CMV end-organ disease in HIV-1-infected individuals despite abundance of highly differentiated CMV-specific CD8+ T-cells

Since CMV-specific T-cells have been shown to generally express an advanced state of differentiation, we investigated whether these mature CMV-specific T-cells are sustained in HIV-infected patients, who are not treated with HAART, receive no CMV medication, but do progress to AIDS with CMV end-organ disease (AIDS-CMV). CD8+ and CD4+ T-cell phenotype was studied in these patients in comparison with long-term asymptomatic HIV-infected individuals, progressors to AIDS without CMV end-organ disease as well as CMV-seropositive HIV-negative controls. CMV-specific CD8+ T-cells from progressors to AIDS-CMV expressed markers typical of highly differentiated effector T-cells, being CCR7-, CD27- CD45RO+/-, with high CD57 expression and increased Ki67 expression, compatible with functional effector cell capabilities. In addition, CD4+ T-cells with the characteristic CD27-CD28- phenotype previously shown to be induced by CMV infection specifically, were found in very high numbers in the HIV+ individuals, but the highest in progressors to AIDS-CMV just before onset of disease. Also the normally rare CD45RO-CD27-CD4+ subset increased significantly, whereas the CD45RO-CD27+CD4+ subset decreased. Our data show that in patients progressing to AIDS-CMV, CMV-specific CD8+ T-cells have expanded and are fully differentiated to mature functional effector T-cells. These cells are not protective apparently, but may contribute to tissue-associated immunopathology characteristic of these clinical conditions.