Serum leptin and CD4+ T lymphocytes in HIV+ children during highly active antiretroviral therapy

objective Because leptin, the adipocyte‐derived hormone, affects thymocyte survival, proliferation of naïve T lymphocytes and the production of proinflammatory cytokines, we aimed to investigate the role of this molecule in immunoreconstitution during highly active antiretroviral therapy (HAART). design Prospective longitudinal cohort study. A series of 20 HIV⁺ children were studied. The subjects were grouped by their increase in serum leptin levels after HAART. methods All participants were weight‐stable, free of endocrine disorders and opportunistic infections and equally distributed for sex (males, n= 10; females, n= 10). Body mass index (BMI), serum lipids, leptin, CD4⁺ T cells and HIV‐1 RNA were measured before initiation of HAART and after a 2‐year follow‐up. results Serum leptin concentration positively correlated with CD4⁺ lymphocyte number before treatment. HAART significantly reduced viraemia and increased serum levels of lipids in all patients, whereas a significant increase in CD4⁺ cells and serum leptin was observed in the majority of patients. Notably, in children where HAART was not effective in increasing CD4⁺ lymphocyte counts, serum leptin did not increase. conclusion To our knowledge, these findings reveal for the first time a novel link among CD4⁺ T lymphocytes, serum leptin and highly active anteretroviral theraphy.     

Naive CD4+ T lymphocytes express high levels of Bcl-2 after highly active antiretroviral therapy for HIV infection

The mechanism causing the increasing number of peripheral T cells after highly active antiretroviral therapy (HAART) is still unclear. The bcl-2 oncogene prevents spontaneous apoptosis (SA) in lymphocytes. Spontaneous apoptosis could be a determinant of HIV immunodeficiency and can be reversed by HAART including protease inhibitors (PI-HAART). The aims of our study were to measure Bcl-2 protein expression in memory (CD45RO+) and naive (CD45RO-) CD4+ and CD8+ T lymphocytes of HIV+ patients and to correlate it with efficacy of PI-HAART. Forty-nine HIV+ patients (cases) and 26 HIV- individuals (controls) were evaluated. Patients receiving PI-HAART, and who had undetectable HIV plasma viral load (VL-, n = 21), had higher levels of Bcl-2 than did VL+ patients (n = 28), both in CD4+ cells (p < 0.0001) and in CD8+ cells (p < 0.001). VL+ patients had lower Bcl-2 levels than did controls in CD8+ cells (p = 0.02), but not in CD4+ cells (p > 0.05). Interestingly, VL- patients had higher Bcl-2 expression than did controls both in CD4+ cells (p < 0.0001) and in CD8+ cells (p = 0.03). In a subcohort of the same patients, Bcl-2 was significantly higher in VL- patients (n = 10) than in controls (n = 12), both in naive CD4+ cells (p < 0.0001) and in naive CD8+ cells (p = 0.01). Naive CD4+ cells had higher Bcl-2 expression in VL- than in VL+ patients (p = 0.01). In a subsequent longitudinal study of nine HIV patients, naive CD4+ cells increased after effective PI-HAART (p = 0.03), which paralleled an increase in Bcl-2 expression in the same cells (p = 0.02). In conclusion, upregulation of bcl-2 could be a mechanism of immune reconstitution of naive CD4+ T cells induced by PI-HAART.     

Reduced CD127 expression on peripheral CD4+ T cells impairs immunological recovery in course of suppressive highly active antiretroviral therapy

Inefficient immune recovery under highly active antiretroviral therapy (HAART) represents a clinical issue. Twenty-seven of 121 HIV+ na?ve patients became immunological nonresponders (INRs) and 55 introduced therapy late [very late treated (VLT)]. INR displayed older age, lower CD4(+) cell counts, down-regulation of CD127(+)CD4(+) and higher apoptotic CD95(+)CD8(+). VLT also showed higher activated CD38(+)CD8(+)%. The only factor associated with INR status was CD127(+)CD4(+)%. INR showed lower baseline interleukin (IL)-7 levels and a reduced expression of IL-7R (CD127(+)) on na?ve and memory T-cells, reaching significance in memory CD127(+)CD45(+)R0(+)CD4(+). These results suggest a possible role for the IL-7/IL-7R system in the pathogenesis of poor immunological recovery during HAART.     

Early highly active antiretroviral therapy for acute HIV-1 infection preserves immune function of CD8+ and CD4+ T lymphocytes

Highly active antiretroviral therapy (HAART) has been advocated for the management of primary HIV-1 infection without clear understanding of its immunological effects. Here, we demonstrate that early use of HAART during primary infection preserves HIV-specific CD8(+) T cells physically and functionally while HIV-specific T cell help is sustained. We also show that even transient administration of HAART at seroconversion can preserve HIV-specific immunity. In contrast, delayed initiation of HAART is associated with a progressive loss of HIV-specific CD8(+) T cells and absent HIV-specific T cell help. These results imply that HIV-specific T help is damaged during primary HIV-1 infection. Early drug treatment, which preserves this immunity, also preserves HIV-specific CD8(+) T cells. These results have implications for understanding the early pathogenesis of HIV-1 infection and suggest that acute HIV infection should be treated aggressively and as early as possible.     

AIDS患者高效抗逆转录病毒联合治疗后外周血CD+8 CD+38T细胞与病毒载量同步变化

目的了解艾滋病(AIDS)患者高效抗逆转录病毒联合治疗(HAART)前后外周血CD+38抗原在CD+8T淋巴细胞上的表达情况.方法应用流式细胞仪采用双色荧光抗体检测技术检测CD+8 CD+38 T细胞;用罗式核酸扩增荧光定量聚合酶链反应(PCR)法检测血浆病毒载量(VL).结果 HAART后2周内CD+8 CD+38 T细胞数与VL开始同步下降,12周后83%AIDS患者的VL降至＜500拷贝/ml,同时CD+8 CD+38 T细胞计数与治疗前相比非常明显地降低(P＜0.001).而且63%的AIDS患者在血浆VL低于检测水平时,其CD+8 CD+38 T细胞数仍继续下降(与VL开始达到检测水平以下时相比,P＜0.001).结论 AIDS患者在HAART开始后,CD+8 CD+38 T细胞数与VL快速下降,在24周左右降至正常水平;并且CD+8 CD+38 T细胞数在VL达到检测不到时仍继续下降,提示在血浆VL低于检测水平时,CD+8 CD+38 T细胞数能够作为判断病毒是否复制的标记.     

Recruitment of Mycobacterium tuberculosis specific CD4+ T cells to the site of infection for diagnosis of active tuberculosis

Context. Accurate and early diagnosis of active tuberculosis (TB) is problematic as current diagnostic methods show low sensitivity (acid‐fast bacilli smears), are time‐consuming (culture of biological samples) or show variable results [Mycobacterium tuberculosis (MTB)‐specific PCR]. Objectives. In the course of infection, MTB‐specific T cells clonally expand at the site of infection and may thus be used as diagnostic marker for active disease. Design. In this cohort study, the frequency of MTB‐specific, interferon (IFN)‐γ expressing CD4⁺ T cells obtained from peripheral blood and the site of disease in 25 patients with suspected TB was assessed (n = 11, bronchoalveolar lavage; n = 7, pleural fluid; n = 1, ascites; n = 1, joint fluid; n = 5, cerebrospinal fluid). Results. Amongst 15 patients who showed proven active TB infection, a striking increase of MTB‐specific T cells was detected at the site of infection compared with peripheral blood (median increase: 28.5‐fold, range: 7.25–531 fold; median of IFN‐γ‐producing CD4⁺ T cells from blood: 0.02%, range: 0–0.52%; median of IFN‐γ‐producing CD4⁺ T cells from the site of infection: 1.81%, range: 0.29–6.55%, P < 0.001). Main outcome measure. Recruitment of MTB‐specific T cells to the site of infection yielded a sensitivity of 100% and specificity of 90%, irrespective of the compartment affected. Conclusions. The accumulation of MTB‐specific T cells at the site of infection may prove as useful diagnostic marker for an accurate and rapid diagnosis of active TB.     

Antigen-driven CD4+ T cell and HIV-1 dynamics: residual viral replication under highly active antiretroviral therapy

Antigen-induced stimulation of the immune system can generate heterogeneity in CD4+ T cell division rates capable of explaining the temporal patterns seen in the decay of HIV-1 plasma RNA levels during highly active antiretroviral therapy. Posttreatment increases in peripheral CD4+ T cell counts are consistent with a mathematical model in which host cell redistribution between lymph nodes and peripheral blood is a function of viral burden. Model fits to patient data suggest that, although therapy reduces HIV replication below replacement levels, substantial residual replication continues. This residual replication has important consequences for long-term therapy and the evolution of drug resistance and represents a challenge for future treatment strategies.     

Unrecognised tuberculosis at antiretroviral therapy initiation is associated with lower CD4+ T cell recovery

Objectives To investigate whether an unrecognised diagnosis of tuberculosis (TB) at the start of antiretroviral therapy (ART) influences subsequent CD4+ T cell (CD4) count recovery in an urban HIV clinic in Uganda. Methods In a retrospective cohort study, a multivariable polynomial mixed effects model was used to estimate CD4 recovery in the first 96 weeks of ART in two groups of patients: prevalent TB (started ART while on TB treatment), unrecognised TB (developed TB within 6 months after start ART). Results Included were 511 patients with a median baseline CD4 count of 57 cells/mm³ (interquartile range: 22–130), of whom 368 (72%) had prevalent TB and 143 (28%) had unrecognised TB. Compared with prevalent TB, unrecognised TB was associated with lower CD4 count recovery at 96 weeks: ?22.3 cells/mm³ (95% confidence interval ?43.2 to ?1.5, P = 0.036). These estimates were adjusted for gender, age, baseline CD4 count and the use of zidovudine‐based regimen. Conclusions Unrecognised TB at the time of ART initiation resulted in impaired CD4 recovery compared with TB treated before ART initiation. More vigilant screening with more sensitive and rapid TB diagnostics prior to ART initiation is needed to decrease the risk of ART‐associated TB and sub‐optimal immune reconstitution.     

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.     

Diagnostic accuracy of CD4 cell count increase for virologic response after initiating highly active antiretroviral therapy

OBJECTIVE: To derive and internally validate a clinical prediction rule for virologic response based on CD4 cell count increase after initiation of HAART in a resource-limited setting. DESIGN AND METHODS: A retrospective cohort study at two HIV care clinics in Gaborone, Botswana. The participants were previously treatment-naive HIV-1-infected individuals initiating HAART. The main outcome measure was a plasma HIV-1 RNA level (viral load) < or = 400 copies/ml (i.e. undetectable) 6 months after initiating HAART. RESULTS: The ability of CD4 cell count increase to predict an undetectable viral load was significantly better in those with baseline CD4 cell counts < or = 100 cells/microl [area under the ROC curve (AUC), 0.78; 95% confidence interval (CI), 0.67-0.89; versus AUC, 0.60; 95% CI, 0.48-0.71; P = 0.018]. The sensitivity, specificity, and positive and negative predictive values of a CD4 cell count increase of > or = 50 cells/microl for an undetectable viral load in those with baseline CD4 cell counts < or = 100 cells/microl were 93.1, 61.3, 92.5 and 63.3%, respectively. Alternatively, these values were 47.8, 87.1, 95.0 and 24.5%, respectively, if a increase in CD4 cell count of > or = 150 cells/microl was used. CONCLUSIONS: CD4 cell count increase after initiating HAART has only moderate discriminative ability in identifying patients with an undetectable viral load, and the predictive ability is higher [corrected] in patients with lower baseline CD4 cell counts. Although HIV treatment programs in resource-constrained settings could consider the use of CD4 cell count increases to triage viral load testing, more accurate approaches to monitoring virologic failure are urgently needed.     

CD4+ cell-count-guided treatment interruptions in chronic HIV-infected patients with good response to highly active antiretroviral therapy

OBJECTIVE: To evaluate the safety of treatment interruption guided by CD4+ cell count in HIV-infected patients followed up prospectively. METHODS: Patients on highly active antiretroviral therapy with CD4+ cell counts > 500 x 10(6) cells/l discontinued therapy with instructions to start therapy again before their CD4+ count dropped below 200 x 10(6) cells/l. Any patients who resumed therapy would be eligible to interrupt treatment again once their CD4+ cell count increased above 500 x 10(6) cells/l. RESULTS: Data on 71 HIV infected patients is reported. Their median nadir CD4+ cell count before antiretroviral treatment was 352 x 10(6) cells/l [interquartile range (IQR), 294-445 x 10(6) cells/l]. The median CD4+ cell count at the time of first interruption was 790 x 10(6) cells/l (IQR, 657-1041 x 10(6) cells/l). The median follow-up after starting the first treatment interruption was 28.3 months (IQR, 21.4-37.0 months). During the follow-up 49 patients restarted therapy and 22 patients remain off therapy; 24 patients have interrupted therapy twice, nine patients have interrupted therapy three times and six patients four times. No AIDS-defining illnesses occurred during the follow-up. The median duration of the first interruption was 15 months (IQR, 6-26 months). The overall reduction of time on therapy was 71.1%. The duration of the first interruption and the reduction of time on therapy were related to nadir CD4+ cell count. The patients who resumed HAART rapidly regained CD4+ cells and achieved viral suppression. CONCLUSION: If carefully monitored, treatment interruptions guided by CD4+ cell count in patients with an initially high CD4+ cell counts are clinically safe, decrease exposure to the drugs and do not reduce the efficacy of therapy when this is re-started.     

Tetanus vaccination with IL-2 during highly active antiretroviral therapy induces sustained and pronounced specific CD4 T-cell responses

HIV-1 infection results in profound dysfunction of the CD4 T-cell population. Although highly active antiretroviral therapy allows the reconstitution of CD4 T-cell numbers, functional abnormalities remain, including inadequate responses to vaccination. IL-2 increases CD4 T-cell numbers and function. We report the effects of IL-2 given with tetanus vaccination in two patients in a larger immunotherapy study. In one case IL-2 induced sustained responses, which may have been caused by the timing of IL-2 with vaccination.     

Long-term changes in circulating CD4 T lymphocytes in virologically suppressed patients after 6 years of highly active antiretroviral therapy

Highly active antiretroviral therapy (HAART) initiated in advanced HIV disease is associated with CD4 lymphocyte increases (200-300 cells/mm3 after 2-4 years), although longer-term cellular dynamics have not been studied. We observed a significant median CD4 lymphocyte increase of 126 cells/mm3 and 54 naive CD4 lymphocytes from year 3 to 6 of HAART among 20 individuals with pre-HAART CD4 cell counts of 100-300 cells/mm3. This cohort represents the longest prospective immunological follow-up of virologically suppressed patients on HAART.     

Incomplete immune reconstitution after initiation of highly active antiretroviral therapy in human immunodeficiency virus-infected patients with severe CD4+ cell depletion

Immune function was observed for 144 weeks in 643 human immunodeficiency virus (HIV)-infected subjects who (1) had nadir CD4+ cell counts of <50 cells/mm3, followed by a sustained increase to > or =100 cells/mm3 after the initiation of HAART, and (2) were enrolled in a randomized trial of continued azithromycin prophylaxis versus withdrawal for prevention of Mycobacterium avium complex disease. The median CD4+ cell count was 226 cells/mm3 at entry and 358 cells/mm3 at week 144. Anergy (80.2% of patients) and lack of lymphoproliferative response to tetanus toxoid (TT; 73%) after immunization and impaired antibody responses after receipt of hepatitis A (54%) and TT (86%) vaccines were considered to be evidence of impaired immune reconstitution. Receipt of azithromycin did not have an effect on CD4+ cell count but was associated with higher rates of delayed-type hypersensitivity responses to TT (25% of subjects who received azithromycin vs. 15% of those who did not; P=.009) and mumps skin test antigen (29% vs. 17%; P=.001). Although the subjects had only partial responses to immune function testing, the rate of opportunistic infections was very low, and none of the tests was predictive of risk.     

Dysregulation of CD28 and CTLA-4 expression by CD4 T cells from previously immunodeficient HIV-infected patients with sustained virological responses to highly active antiretroviral therapy

OBJECTIVES: Current guidelines recommend commencing highly active antiretroviral therapy (HAART) in HIV-infected patients when CD4 T-cell counts reach 350 cells/microL. However, late-presenting HIV-infected patients with CD4 T-cell counts<50 cells/microL are still common. The ability of long-term HAART to normalize immune dysregulation in severely immunodeficient HIV-infected patients remains unclear. Here we address indices of immune dysregulation in previously severely immunocompromised HIV-infected patients treated with long-term HAART who had achieved increased CD4 T-cell counts and complete suppression of HIV viraemia. METHODS: We examined expression of CD28, cytotoxic T-lymphocyte antigen-4 (CTLA-4) and intracellular perforin by CD4 and CD8 lymphocytes from 25 highly selected HIV-infected patients [nadir CD4 T-cell counts <50 cells/microL, >4 years on HAART and >6 months of complete viral suppression (<50 HIV-1 RNA copies/mL)] and 18 HIV-seronegative age- and sex-matched controls. RESULTS: HIV-infected patients had lower percentages of CD28-expressing CD4 lymphocytes and higher percentages of CTLA-4-expressing CD4 lymphocytes than controls. The percentage of CTLA-4-expressing CD4 lymphocytes correlated inversely with that of CD28-expressing CD4 lymphocytes. The proportion of CD4 lymphocytes expressing perforin was generally low. However, more HIV-infected patients than controls had >1% of CD4 lymphocytes expressing perforin [11 of 25 (44%) vs. one of 18 (5.5%)]. The percentage of CD8 lymphocytes expressing perforin did not differ between HIV-infected patients and controls. Amongst HIV-infected patients, the percentage of perforin-expressing CD8 lymphocytes correlated inversely with nadir but not current CD4 T-cell count. CONCLUSIONS: Expression of CD28, CTLA-4 and perforin by CD4 lymphocytes remain dysregulated in HIV-infected patients with previous severe immunodeficiency, despite increased CD4 T-cell counts and control of HIV viraemia by HAART.     

Region of difference 1 antigen-specific CD4+ memory T cells correlate with a favorable outcome of tuberculosis

BACKGROUND: Interferon (IFN)-gamma response to region of difference (RD) 1 proteins (culture filtrate 10 and early secreted antigenic target 6) or overlapping peptides is a novel diagnostic marker of tuberculosis (TB) infection. Because we have recently shown that the response to certain peptides selected from RD1 allows discrimination between active TB (A-TB) and successfully treated TB (T-TB), we analyzed here the effector memory T cell profile and RD1-specific responses under the same clinical conditions. METHODS: T cell responses to RD1 antigens were analyzed in patients with either severe or mild A-TB (classified on the basis of radiological lesions) and in 2 sets of healthy control subjects--those who had been successfully treated (the T-TB control subjects) and those whose tuberculin skin test (TST) results were negative (the TST-negative control subjects). IFN-gamma -producing CD4+ effector T cells were monitored by flow-cytometric analysis and ex vivo enzyme-linked immunospot (ELISPOT) assay, whereas a "cultured" ELISPOT assay was used to determine the frequency of memory T cells. RESULTS: In the patients with severe A-TB, both CD4-mediated effector memory and central memory responses to the selected RD1 peptides were almost absent, whereas these responses were found in the majority of the patients with mild A-TB. In contrast, recognition of the selected RD1 peptides was detected in the T-TB control subjects only by expanding the central memory T cell pool. CONCLUSIONS: These data suggest a protective role for RD1 peptide-specific CD4+ effector T cells, which undergo clonal expansion during Mycobacterium tuberculosis replication and then a contraction phase after disease resolution, culminating in the generation of CD4+ memory T cells.     

Impact of HIV-1 infection and highly active antiretroviral therapy on the kinetics of CD4+ and CD8+ T cell turnover in HIV-infected patients

To evaluate the effects of HIV infection on T cell turnover, we examined levels of DNA synthesis in lymph node and peripheral blood mononuclear cell subsets by using ex vivo labeling with BrdUrd. Compared with healthy controls (n = 67), HIV-infected patients (n = 57) had significant increases in the number and fraction of dividing CD4(+) and CD8(+) T cells. Higher percentages of dividing CD4(+) and CD8(+) T cells were noted in patients with the higher viral burdens. No direct correlation was noted between rates of T cell turnover and CD4(+) T cell counts. Marked reductions in CD4(+) and CD8(+) T cell proliferation were seen in 11/11 patients 1-12 weeks after initiation of highly active antiretroviral therapy (HAART). These reductions persisted for the length of the study (16-72 weeks). Decreases in naive T cell proliferation correlated with increases in the levels of T cell receptor rearrangement excision circles. Division of CD4(+) and CD8(+) T cells increased dramatically in association with rapid increases in HIV-1 viral loads in 9/9 patients 5 weeks after termination of HAART and declined to pre-HAART-termination levels 8 weeks after reinitiation of therapy. These data are consistent with the hypothesis that HIV-1 infection induces a viral burden-related, global activation of the immune system, leading to increases in lymphocyte proliferation.     

Frequencies of circulating IL-17-producing CD4+CD161+ T cells and CD4+CD161+ T cells correlate with disease activity in rheumatoid arthritis

Abstract

Objective. Rheumatoid arthritis (RA) is a common autoimmune disease that is primarily driven by effector T cells, particularly Th17 cells, which are mainly contained within CD4+CD161+ T cells. Thus, we aimed to explore whether the frequencies of circulating IL-17-producing CD4+CD161+ T cells and CD4+CD161+ T cells were correlated with RA disease activity.

Methods. The surface phenotype and cytokine production of blood were analyzed by flow cytometry in 52 RA patients and 17 healthy controls. The disease activity was evaluated by the 28-joint disease activity score.

Results. The frequencies of circulating IL-17-producing CD4+CD161+ T cells and CD4+CD161+ T cells were increased in RA patients, and they were elevated in patients with active disease status compared to patients with low disease status. Furthermore, their frequencies were positively correlated with disease activity parameters. Receiver operating characteristic curve analysis revealed that IL-17-producing CD4+CD161+ T cell levels were able to distinguish disease activity with 60.7 % sensitivity and 87.5 % specificity, while CD4+CD161+ T cell levels showed 92.9 % sensitivity and 66.7 % specificity.

Conclusion. These results support the hypothesis that Th17 cells are involved in the pathogenesis of RA and suggest that circulating CD4+CD161+ T cells are a potential biomarker of RA disease activity.