HIV感染者/AIDS患者外周血T细胞抗原受体γδT细胞的检测及其临床意义

目的　探讨外周血T细胞抗原受体 (TCR)γδT细胞在艾滋病病毒 (HIV)感染者 /艾滋病 (AIDS)患者疾病进程中的作用。方法　应用流式细胞仪采用三色荧光抗体染色技术分别检测 18例HIV感染者、2 9例AIDS患者、2 5例伴有机会性感染的AIDS患者、2 0例高效抗逆转录病毒联合疗法 (HAART)治疗后的AIDS患者及 2 0例正常对照者外周血的TCRγδT细胞与TCRαβT细胞。 结果　HIV感染者组和AIDS患者组的外周血TCRγδT细胞的百分率比正常对照组明显地增高 (P <0 0 1) ,而TCRαβT细胞的百分率明显地低于正常对照组 (P <0 0 1) ,AIDS患者组的CD+ 3 细胞的百分率明显地低于HIV感染者组和正常对照组 (P <0 0 1)。AIDS患者伴机会性感染组的外周血TCRγδT细胞的百分率明显地高于HAART治疗后的AIDS患者组 (P <0 0 1) ,该组的TCRαβT细胞的百分率及CD+ 3 T细胞的百分率则明显地低于经HAART治疗后的AIDS患者组 (P <0 0 1)。结论　TCRγδT细胞数量增多是机体受到病毒感染时的一种早期非特异性免疫反应 ,在AIDS的疾病进程中及机会性感染时起一定的免疫防御作用。     

AIDS-related Mycobacterium avium infection dissemination in a patient with endobronchial lesions associated with immune reconstitution inflammatory syndrome

Highly active antiretroviral therapy (HAART) has dramatically decreased the incidence of HIV-1-associated morbidity and mortality. During the initial months of HAART, immune reconstitution inflammatory syndrome (IRIS), an adverse consequence of restoration of the pathogen-specific immune response, often occurred in terminal-stage in patients, with MAC infection the most frequently implicated in IRIS. In August 2004, a 26-year-old Japanese woman with fever and general lymphadenopathy was diagnosed with AIDS (HIV-1 RNA 5.7 x 10(5) copies/mL, CD4+ T cell count 10/microL) and disseminated Mycobacterium avium (M. avium) infection, for which antimycobacterial treatment was initiated. The M. avium infection responded well to two months of this treatment, and HAART was begun. Despite good virologic response to HAART (HIV-1 RNA <50 copies/mL), she contracted pulmonary disease with parenchymal lung changes, endobronchial lesions, and localized supraclavicular lymphadenitis, which are M. avium-associated IRIS. Good immunological response (CD4+ T cell count 136/microL) and a stronger antimycobacterial treatment helped her overcoming M. avium-associated IRIS without systemic corticosteroids or the discontinuation of HAART. The possibility of IRIS should always be watched for when treating AIDS patients with HAART and an antimycobacterial treatment regimen formulated that considers potential drug interactions with HAART.     

Immune restoration disease after the treatment of immunodeficient HIV-infected patients with highly active antiretroviral therapy

Background To determine if infectious disease events in HIV-infected patients treated with highly active antiretroviral therapy (HAART) are a consequence of the restoration of pathogen-specific immune responses, a single-centre retrospective study of all HIV-infected patients commencing HAART prior to 1 July 1997 was undertaken to determine the incidence, characteristics and time of onset of disease episodes in HAART responders (decrease in plasma HIV RNA of > 1 log₁₀ copies/mL).
Methods Baseline and post-therapy changes in CD4 T-cell counts and HIV RNA were compared in patients with and without disease and delayed-type hypersensitivity responses to mycobacterial antigens were measured in selected patients.
Results Thirty-three of 132 HAART responders (25%) exhibited one or more disease episodes after HAART, related to a pre-existent or subclinical infection by an opportunistic pathogen. Disease episodes were most often related to infections by mycobacteria or herpesviruses but hepatitis C virus (HCV), molluscum contagiosum virus and human papilloma virus were also implicated. They were most common in patients with a baseline CD4 T-cell count of < 50/uL and occurred most often during the first 2 months of therapy and when CD4 T-cell counts were increasing. Mycobacteria- and HCV-related diseases were associated with restoration of pathogen-specific immune responses.
Conclusions We conclude that improved immune function in immunodeficient patients treated with HAART may restore pathogen-specific immune responses and cause inflammation in tissues infected by those pathogens.     

Cytomegalovirus (CMV) retinitis immune restoration disease occurs during highly active antiretroviral therapy-induced restoration of CMV-specific immune responses within a predominant Th2 cytokine environment

Plasma levels of cytomegalovirus (CMV)-specific immunoglobulin G (IgG), soluble (s) CD30, sCD26 (dipeptidyl peptidase IV [DPP IV]) enzyme activity, and tumor necrosis factor receptor-I (TNFR-I) were assessed in human immunodeficiency virus (HIV)-infected patients who experienced CMV retinitis (CMVR) as an immune restoration disease (IRD) during their first 6 months of highly active antiretroviral therapy (HAART) and in CMV-seropositive, HIV-infected patients with similar baseline CD4(+) T cell counts who had uneventful immune reconstitution. Patients who experienced CMVR IRD had a significant increase in CMV-specific IgG during their first 12 months of HAART, indicating restored CMV-specific immune responses. They also had significantly higher levels of sCD30 both before HAART and for up to 12 months after start of treatment. sCD30 levels remained elevated during 48 months of HAART, suggesting persistence of a predominant Th2 cytokine environment. Levels of sCD26 (DPP IV) enzyme activity and TNFR-I did not differ significantly between the 2 groups at any time point.     

Varicella-Zoster virus-specific cell-mediated immunity in HIV-infected children receiving highly active antiretroviral therapy

Herpes zoster (HZ) is a frequent complication of advanced human immunodeficiency virus (HIV) infection. We determined the effect of highly active antiretroviral therapy (HAART) on reconstitution of varicella-zoster virus (VZV)-specific cell-mediated immunity (VZV-CMI) in 56 VZV- and HIV-infected children. VZV-CMI did not change over the course of >/=3 years of observation, despite a reduction in HIV load. VZV-CMI correlated with lower HIV load but not with CD4 cell percentage. The incidence of HZ was unaffected by HAART. None of 5 patients who developed HZ during the study had VZV-CMI before developing HZ. After developing HZ, only the 2 HAART-compliant patients developed VZV-CMI. Thus, VZV-specific immune reconstitution in HIV infection may require antigenic reexposure, in addition to control of HIV replication.     

HAART治疗中免疫功能恢复不完全者的中医药干预

目的明确中医药改善艾滋病（AIDS）病人免疫功能、促进免疫重建的积极作用,为中医药介入高效抗反转录病毒治疗（HAART）的必要性提供科学依据。方法选取21例经HAART后病毒载量控制理想、但免疫功能恢复不完全的AIDS病人,给予介入中医药治疗并观察疗效。结果 21例经单纯HAART后,CD4＋T淋巴细胞计数升高不明显的病人,在介入＂康爱保生胶囊＂进行中西药合用治疗后,CD4＋T淋巴细胞上升〉50/mm3者17例（占80.95%）,上升〈50/mm3者2例（占9.52%）,下降者2例（占9.52%）。21例病人治疗后CD4＋T淋巴细胞计数较治疗前上升（167.14±38.89）/mm3,上升比例达94.37%。结论在HAART有效控制病毒载量的基础上,积极介入中药治疗,将有助于促进病人免疫功能的重建,大大增强HAART的疗效,对提高病人生存质量、降低病死率有重要意义。     

The prevalence and risk of immune restoration disease in HIV-infected patients treated with highly active antiretroviral therapy

BACKGROUND: It is becoming increasingly clear that, during successful highly active antiretroviral therapy (HAART), a proportion of treated patients develop opportunistic infections (OIs), referred to in this setting as immune restoration disease (IRD). We examined the risk of developing IRD in HAART-treated HIV-infected patients. METHODS: A retrospective study of a cohort including all 389 patients treated with HAART between 1 January 1998 and 31 May 2004 in our HIV unit was performed to evaluate the occurrence of and risk factors for IRD during HAART. Baseline and follow-up values of CD4 T-cell counts and plasma viral loads (pVLs) were compared to assess the success of HAART. RESULTS: During successful HAART (significant increase in CD4 T-cell counts and decrease in pVL), at least one IRD episode occurred in 65 patients (16.7%). The median time to IRD was 4.6 months (range 2-12 months). IRDs included dermatomal herpes zoster (26 patients), pulmonary tuberculosis (four patients), tuberculous exudative pericarditis (two patients), tuberculous lymphadenitis (two patients), cerebral toxoplasmosis (one patient), progressive multifocal leucoencephalopathy (PML) (one patient), inflamed molluscum (one patient), inflamed Candida albicans angular cheilitis (three patients), genital herpes simplex (two patients), tinea corporis (two patients), cytomegalovirus (CMV) retinitis (two patients), CMV vitritis (one patient) and hepatitis B (three patients) or C (fifteen patients). A baseline CD4 T-cell count below 100 cells/microL was shown to be the single predictor [odds ratio (OR) 2.5, 95% confidence interval (CI) 0.9-6.4] of IRD, while a CD4 T-cell count increase to >400 cells/microL, but not undetectable pVL, was a negative predictor of IRD (OR 0.3, 95% CI 0.1-0.8). CONCLUSIONS: To avoid IRD in advanced patients, HAART should be initiated before the CD4 T-cell count falls below 100 cells/microL.     

Development of multiple abscesses in an HIV/TB co-infected patient after initiation of antituberculous and highly active antiretroviral therapy

Since the use of Highly Active Antiretroviral Therapy (HAART) for HIV infection, there have been increasing reports of systemic manifestations of immune restoration. This new clinical syndrome among HIV-infected patients is associated with underlying co-infections with mycobacteria, cytomegalovirus, hepatitis B and C infections, etc.... We report on an HIV/tuberculosis (TB) co-infected patient who developed an immune restoration inflammatory syndrome after initiation of HAART and anti-TB treatment. She developed fever, large abscesses and pleural and peritoneal effusions. Systemic symptoms decreased during corticosteroid treatment, but abscesses only disappeared 8 months after the start of the anti-TB treatment.     

AIDS抗病毒治疗6个月内机会性感染的变化和分布状况

目的 探讨对AIDS患者进行高效抗反转录病毒治疗6个月内机会性感染的变化和分布状况.方法 使用统一的调查表进行回顾性和前瞻性研究.调查表的内容涉及患者编号、性别、年龄、治疗开始时间、治疗方案、开始抗病毒治疗前3个月、治疗后2周内、2周～3个月和3～6个月出现机会性感染的情况及基线、治疗3个月和治疗6个月CD4+T淋巴细...     

Safety of vaccinating sibling donors with live-attenuated varicella zoster vaccine before hematopoietic stem cell transplantation

Reactivation of varicella zoster virus (VZV), clinically manifested as herpes zoster (HZ) is a common complication after hematopoietic stem cell transplantation (HSCT). The optimum prophylaxis for this disease has not been defined. In this study, we examined the effects of vaccinating donors with a live-attenuated vaccine with particular reference to their immune responses and the outcome of HSCT patients. Forty prospective HLA-matched sibling donors were vaccinated before HSCT. There were humoral immune responses in both sero-positive (P<0.01) and sero-negative (P=0.058) donors. Cellular immune response was assayed in 26 donors. Significant correlation was observed between cellular immune responses as enumerated by thymidine incorporation and interferon gamma secretion (P<0.001) and the latter was used in subsequent analyses. Significant response was observed in sero-negative (6/26) and a group of sero-positive (13/26) donors while 7/26 sero-positive donors showed no response. Thirty-four HSCT were performed. These patients have a lower, albeit insignificant, risk of HZ compared with historical controls and only 3/34 patients developed single dermatomal HZ at 6, 9 and 28 months after HSCT. No patients developed VZV-related mortality. Vaccinating donors with live-attenuated VZV vaccine was safe, but whether it confers a significant protection to the patients would require further study.     

Recurrence of Mycobacterium avium infection in patients receiving highly active antiretroviral therapy and antimycobacterial agents.

The known effects of highly active antiretroviral therapy (HAART) on opportunistic infections (OIs) range from immune restoration disease to remission of specific OIs. In the present study, Mycobacterium avium complex infection recurred in 3 patients receiving antimycobacterial therapy and HAART. At the time of the initial M. avium infection, the mean CD4 cell count was 22.3 cells/mm3, and the HIV viral load was 181,133 copies/mL. Relapse occurred a mean of 14. 3 months after the first episode; the mean follow-up CD4 cell count was 89/mm3 (mean elevation of 66 cells/mm3), and the HIV viral load was <400 copies/mL in each patient. M. avium was isolated from blood (1 patient), blood and lymph node (1), and small-bowel tissue (1). M. avium infection may recur as a generalized or focal disease in those who are receiving antimycobacterial agents but whose HAART-associated CD4 cell recovery, although significant, is not optimal.     

AIDS-defining illnesses: a comparison between before and after commencement of highly active antiretroviral therapy (HAART)

Attempts to address the significant impact of HAART on medical variables on the Malaysian HIV/AIDS population have yet to be evaluated. This study aims to analyze the proportions of AIDS-defining illnesses (ADIs) before and after HAART. A retrospective study was carried out on 128 new cases of HIV infected patients who first commenced HAART in 2004 at the national HIV reference center. Before commencement of HAART, 76 clinical episodes of ADIs were recorded in 52 patients. Most common being pulmonary Mycobacterium tuberculosis (28.9%), PCP (27.6%) and disseminated and extrapulmonary Mycobacterium tuberculosis (11.8%). During HAART, 8 clinical episodes of ADIs were documented in 7 patients with a median time of onset of 10 weeks after initiation of HAART (range, 4-36 weeks). The median CD4 count at the time of the commencement of HAART for these patients was 11 cells/mm(3). ADIs reported include PCP (2 episodes), disseminated and extrapulmonary Mycobacterium tuberculosis (2 episodes), extrapulmonary cryptococcosis (1 episode), esophageal candidiasis (1 episode), recurrent pneumonia (1 episode) and disseminated or extrapulmonary histoplasmosis (1 episode). Three (37.5%) of these occurred despite a reduction of viral load by at least 2 log(10) and an increased in the CD4 cell count. In conclusion, ADIs can still present after the initiation of successful HAART especially in those with CD4 counts below 100 cells/mm(3). In Malaysia, ADIs are the major causes of HIV/AIDS associated morbidity and mortality, thus increased awareness on the management of these illnesses is warranted especially in the months following HAART.     

Sequential occurrence of thyroid autoantibodies and Graves' disease after immune restoration in severely immunocompromised human immunodeficiency virus-1-infected patients

We analyzed the kinetics of CD4 cells, human immunodeficiency virus (HIV) viral load, and autoantibodies in acquired immune deficiency syndrome patients with Graves' disease (GD) after immune restoration on highly active antiretroviral therapy (HAART; retrospective study). Five patients (median age, 41 yr) were diagnosed with GD after 20 (range, 14-22) months on HAART on the basis of clinical and biological hyperthyroidism, diffuse hyperfixation of thyroid scan, and the presence of anti-TSH receptor (anti-TSHR) antibodies (Ab). GD was diagnosed several months after the plasma HIV ribonucleic acid load became undetectable, when the CD4+ cell count had risen from 14 (range, 0-62) to 340 (range, 163-460) x 10(6) cells/L. Antithyroid peroxidase (anti-TPO) and anti-TSHRAb appeared 14 (range, 9-18) and 14 (range, 11-20) months after starting HAART and 12 (range, 6-15) and 11 (range, 9-17) months after the increase in CD4+ cells. In 3 patients, TPOAb preceded TSHRAb by 3-10 months. No other autoantibodies were detected. Thyroid antibodies were absent in a group of 55 HIV-1-positive patients with comparable response to HAART and no symptoms of hyperthyroidism (cross-sectional study). Thyroid-specific autoimmunity can occur upon immune restoration with HAART. Our observations suggest a relationship between thymus-dependent immune reconstitution after immunosuppression and autoimmunity and may provide insight into the pathophysiology of GD.     

Restoration of normal interleukin-2 production by CD4+ T cells of human immunodeficiency virus-infected patients after 9 months of highly active antiretroviral therapy.

The present study investigated immune restoration in patients at intermediate stages of human immunodeficiency virus (HIV) disease after initiation of highly active antiretroviral therapy (HAART). A progressive increase in both memory and naive CD4+ T cells was observed from the first weeks of therapy, concomitant with a decrease in the expression of activation markers on CD8+ T cells. The early-activation marker CD69 remained, however, overexpressed on T cells after suboptimal stimulation in vitro, indicative of persistent immune activation. The percentage of interleukin (IL)-2-producing CD4+ T cells significantly increased from 9 months of HAART. In most patients, CD4+ T cells recovered an ability to produce IL-2 on stimulation, similar to that of HIV-seronegative controls. Reversal of T-cell anergy may be a key event in immune restoration for achieving long-term clinical benefit with HAART.     

Long-term survival of HIV-infected patients treated with highly active antiretroviral therapy in Serbia and Montenegro

BACKGROUND: Highly active antiretroviral therapy (HAART) has dramatically changed the prognosis of HIV disease, even in terminally ill patients. Although these patients may survive many years after the diagnosis of AIDS if treated with HAART, some still die during treatment. METHODS: A retrospective study in a cohort of 481 HIV-infected patients treated with HAART between January 1998 and December 2005 was conducted to compare subgroups of long-term survivors (LTSs) and patients who died during treatment. RESULTS: A total of 48 patients survived for more than 72 months (mean 83.8+/-standard deviation 5.6 months). Thirty patients died during treatment (mean 35.3+/-25.0 months), of whom nine died from non-AIDS-related causes, 18 died from AIDS-related causes, and three died as a result of HAART toxicity. Although LTSs were significantly (P=0.015) younger at HAART initiation, age below 40 years was not a predictor of long-term survival. The subgroups did not differ in the proportion of clinical AIDS cases at HAART initiation, in the prevalence of hepatitic C virus (HCV) coinfection, or in pretreatment and end-of-follow-up CD4 cell counts. In contrast, the viral load achieved during treatment was lower in the survivors (P=0.03), as was the prevalence of hepatitis B virus (HBV) coinfection (P=0.03). Usage of either protease inhibitor (PI)-containing regimens [odds ratio (OR) 9.0, 95% confidence interval (CI) 2.2-35.98, P<0.001] or all three drug classes simultaneously (OR 7.4, 95% CI 2.2-25.1, P<0.001) was associated with long-term survival. Drug holidays incorporated in structured treatment interruption (STI) were also associated with a good prognosis (OR 14.9, 95% CI 2.9-75.6, P<0.001). CONCLUSIONS: Long-term survival was associated with PI-based HAART regimens and lower viraemia, but not with the immunological status either at baseline or at the end of follow up. STI when CD4 counts reach 350 cells/microL, along with undetectable viraemia, was a strong predictor of long-term survival.     

Whole brain radiation alone produces favourable outcomes for AIDS‐related primary central nervous system lymphoma in the HAART era

Primary central nervous system lymphoma (PCNSL) related to acquired immunodeficiency syndrome (AIDS) is a lethal disorder, but the recent application of highly active antiretroviral therapy (HAART) has significantly improved prognosis. This retrospective cohort study of AIDS‐related PCNSL examined the actual clinical outcomes and prognostic variables affecting overall survival (OS) in the HAART era. Twenty‐three newly diagnosed AIDS‐related PCNSL at 12 regional centre hospitals for HIV/AIDS in Japan between 2002 and 2008 were consecutively enrolled. The estimated 3‐yr OS rate of the entire cohort was 64% (95%CI, 41.0–80.3%). Whole brain radiation therapy (WBRT) had an independent positive impact on survival (WBRT ≥30 Gy vs. others, P = 0.02). Nine of 10 patients with a good performance status (PS) (0–2) remained alive with complete response, whereas 10 (77%) of 13 of those with a poor PS (3–4) died mostly after a short period. The estimated 3‐yr OS rate of the groups with a good and poor PS was 100% and 38% (95%CI, 14–63%), respectively (P = 0.01). Leukoencephalopathy (grade ≥ 2) developed in 21% of those that survived more than 12 months after radiation. The patients receiving a curative intent radiation dose (≥30 Gy) of WBRT achieved prolonged survival while maintaining a good quality of life in the HAART era, especially among patients with a favourable PS.     

Immune reconstitution disease associated with mycobacterial infections in HIV-infected individuals receiving antiretrovirals

Immune reconstitution disease (IRD) in HIV-infected patients is an adverse consequence of the restoration of pathogen-specific immune responses during the initial months of highly active antiretroviral treatment (HAART). Previously subclinical infections are "unmasked" or pre-existing opportunistic infections clinically deteriorate as host immunopathological inflammatory responses are "switched on". IRD is most frequently associated with mycobacterial infections. Our literature search identified 166 published cases of IRD associated with mycobacterial infections. We review the underlying immunological mechanisms, difficulties surrounding case definition and diagnosis, the wide diversity of clinical manifestations, and treatment. The importance of screening patients for mycobacterial disease before starting HAART and the critical impact of the timing of commencement of HAART in patients receiving treatment for tuberculosis are highlighted. We also discuss the problem of IRD associated with mycobacterial diseases in developing countries where tuberculosis prevalence is high and access to HAART is currently expanding.     

Soft tissue abscess and lymphadenitis due to Mycobacterium avium complex as an expression of immune reconstitution inflammatory syndrome after a second scheme of highly active antiretroviral therapy

Immune reconstitution inflammatory syndrome (IRIS) is an atypical and unexpected reaction related to highly active antiretroviral therapy (HAART) in human immunodeficiency virus (HIV) infected patients. IRIS includes an atypical response to an opportunistic pathogen (generally Mycobacterium tuberculosis, Mycobacterium avium complex, cytomegalovirus and herpes varicella-zoster), in patients responding to HAART with a reduction of plasma viral load and evidence of immune restoration based on increase of CD4+ T-cell count. We reported a case of a patient with AIDS which, after a first failure of HAART, developed a subcutaneous abscess and supraclavicular lymphadenitis as an expression of IRIS due to Mycobacterium avium complex after starting a second scheme of HAART.     

Recovery of hematopoietic activity in bone marrow from human immunodeficiency virus type 1-infected patients during highly active antiretroviral therapy

The mechanisms responsible for the hematopoietic failure in human immunodeficiency virus type 1 (HIV-1)-infected patients are still unknown. Several findings indicate that the in vitro proliferative potential of precursor cells from AIDS patients is reduced. The changes seen in bone marrow (BM) morphology and the defective BM functions associated with cytopenias have both been proposed as potential explanations. In patients treated with highly active antiretroviral therapy (HAART) an immune reconstitution associated with increased whole blood cell counts has been described. We have investigated the effects of HAART on the number of colony-forming cells (CFCs) and long-term culture-initiating cells (LTC-ICs), using long-term BM cell cultures (LTBMC) in a group of subjects with HIV-1 infection enrolled in an open study to evaluate the mechanisms of immune reconstitution during HAART. In each patient, the increase in colony growth was homogeneous, regardless of the type of hematopoietic progenitor cells assayed; in four subjects an increase in the most primitive progenitor cells (LTC-ICs) was observed. These findings were associated with the in vivo data showing increased numbers of BM mononuclear cells (BMMCs) after HAART and with a rise in peripheral CD4(+) T cell counts and decreased levels of plasma HIV-1 RNA. A decreased number of hematopoietic progenitor cells and/or a defective modulation of progenitor cell growth might be the cause of the hematological abnormalities in AIDS patients. Controlling HIV-1 replication by HAART could determine a restoration of stem cell activity, probably because of the suppression of factors that inhibit normal hematopoiesis.