Dynamics of T cells subsets and lymphoproliferative responses during structured treatment interruption cycles and after definitive interruption of HAART in early chronic HIV type-1-infected patients

Little is known about the consequences of short cycles of structured treatment interruption or definitive interruption of HAART for both T cell subset dynamics and T lymphoproliferative responses (LPR). Immunological follow-up was performed in 45 early chronical HIV-1-infected patients during short STI cycles during the first 12 weeks after the definitive interruption of HAART (DTI) and, thereafter, until VL reached a plateau. During STI cycles, CD8(+), CD8(+), CD28(+), activation markers and naive CD4(+) T cells increased significantly (p < 0.0001), while both naive CD8(+) and memory CD4(+) T cells decreased. During DTI, CD8(+) CD28(+) T cells fell and CD4(+) naive T cells stabilized and the rest of the T cell subsets presented changes similar to those during STI cycles. Despite a transient increase in LPR to recall antigens and HIV proteins during STI cycles, LPR to polyclonal stimuli and pathogens decreased over the study. Differences in T cell subset dynamics and LPR observed throughout the study suggest that multiple exposures to low levels of antigen could improve the immune system, mainly by driving T cell maturation. Conversely, higher and longer viral replication after cessation of HAART overwhelms the immune system. These data may help to guide future immune-based therapies.     

Immune modulatory effects of cyclooxygenase type 2 inhibitors in HIV patients on combination antiretroviral treatment

OBJECTIVES: To examine the immune modulating effects of cyclooxygenase type 2 (COX-2) inhibitors (COX-2i) in HIV-infected patients on combination antiretroviral treatment (CART). DESIGN: In-depth substudy from an approved, open, controlled, randomized study comparing the immune modulating effects of CART in combination with COX-2i after 12 weeks. METHODS: Patients (n = 38) on long-term CART with stable viral load (VL) < 50,000 copies/ml and CD4+ T-cell counts > 100/microl were randomized to CART and rofecoxib 25 mg bid (n = 12) or celecoxib 400 mg bid (n = 12), or CART only without placebo (n = 14). Routine clinical chemistry, CD4+ and CD8+ counts and VL were safety parameters. Immunological parameters included C-reactive protein, beta2-microglobulin, Ig isotypes and IgG subclasses as well as several T-lymphocyte subsets. Non-parametric analyses were used throughout. RESULTS: Prestudy experiments showed higher median intracellular expression of COX-2 in CD4+ (P = 0.048) and possibly CD8+ (P = 0.09) T cells from patients on CART compared with uninfected controls. In the clinical study, increased CD4+ T-cell counts were observed only in patients on COX-2i with VL < 50 copies/ml (P = 0.02). Decreased expression of CD38+ on CD8+ T cells and subsets as well as reductions in IgA and IgM (P < 0.03) were most pronounced in patients on COX-2i who had detectable VL (n = 6). COX-2i treatment enhanced the perforin content particularly in the differentiated CD27-/CD8+ T-cell subsets compared with controls (P = 0.05). CONCLUSIONS: COX-2i together with CART improved markers for persistent immune activation, particularly in patients with viraemia, as well as enhanced perforin expression, and thereby strengthened COX-2 as a potential therapeutic target in HIV infection.     

CD8+ Lymphocyte Decrease in HIV Disease: Association with Anti-CD4+ but Not with Anti-CD8+ Lymphocyte Autoantibodies

HIV+ patients form autoantibodies against CD4+ and CD8+ lymphocytes. It was shown that anti-CD4+ lymphocyte autoantibodies are associated with the depletion of CD4+ cells. In the present study we analyzed the relationship of anti-CD4+ and anti-CDS+ autoantibodies with the CD8+ lymphocyte decrease commonly observed during HIV disease. IgM and IgG antibodies as well as complement fragments were determined on the surface of CD4+ and CD8+ lymphocytes using double fluorescence flow cytometry. Anti-CD8+ lymphocyte autoantibodies were found more often in HIV+ hemophilia patients (75/105 = 71%) than HIV- hemophilia patients (13/37 = 35%; p<0.0001), patients with pharyngeal carcinoma (20/44 = 45%; p = 0.002), habitual abortions (3/13 = 23%; p = 0.0009) or healthy individuals (93/223 = 42%; p< 0.0001). Anti-CD8+ antibodies, mostly of the IgM type, occurred significantly more frequently than anti-CD4+ antibodies in healthy controls (p< 0.0001), patients with pharyngeal carcinoma (p = 0.0001), or HIV- patients (p = 0.01). In HIV+ patients, however, anti-CD4+ autoantibodies were found more often than anti-CD8+ antibodies (85 vs 71%; p = 0.02). 70 of 104 (67%) HIV+ patients had autoantibodies on both CD4+ and CD8+ lymphocytes and the IgG/IgM/C3d autoantibody pattern was identical in 31 (44%) of the patients. Interestingly, peripheral blood CD8+ cell counts were significantly associated with anti-CD4+ (p = 0.01) but not with anti-CD8+ lymphocyte autoantibodies. It is hypothesized that the inhibition and depletion of CD4+ cells by anti-CD4+ autoantibodies is associated with a loss of regulatory functions that leads to a depletion of antiviral cytotoxic CD8+ lymphocytes.     

Retrospective analysis of suspending HAART in selected patients with controlled HIV replication

We sought to determine the consequences of stopping highly active antiretroviral therapy (HAART) in a group of 41 HIV-infected individuals with undetectable HIV viral loads and CD4+ counts greater than 500 cells per microliter for 6 months or more. Clinical and laboratory parameters were monitored, as was the time to HAART reinitiation. Three months after HAART interruption, the median CD4+ count declined by 162 cells per microliter and HIV viral load increased by 24,000 copies per milliliter. Over the next year, CD4+ counts continued to decrease by an average of 11 cells per microliter per 3-month intervals. In contrast, HIV viral loads remained stable over the same period. Five of 7 patients (71%) with elevated cholesterol levels and 6 of 13 patients (46%) with elevated triglyceride levels had these values normalize after stopping HAART. After a median of 21 months follow-up, 26 of 41 patients (63%) have restarted HAART. Patients with Centers for Disease Control (CDC) HIV/AIDS C classification were more likely to restart HAART than those with A or B classification (p = 0.008). Reasons for HAART restart included clinical events in 8 patients. Fifteen patients restarted HAART for immunologic reasons: CD4+ count less than 300 cells per microliter (n = 7); HIV viral load greater than 55,000 copies per milliliter (n = 3); or both (n = 5). Three patients restarted HAART because of personal preference. Within 4 months, all 26 patients who restarted HAART achieved HIV viral loads less than 50 copies per milliliter. Although patients were able to rapidly achieve nondetectable HIV viral loads after restarting HAART, the inability to foresee clinical events among 8 patients (20%) is disconcerting. We advise caution before HAART interruption, particularly for those patients with a preceding history of significant HIV-related complications.     

Persistent low viral load on antiretroviral therapy is associated with T cell-mediated control of HIV replication

BACKGROUND: It is unclear how stable low-level viral replication and CD4 cell numbers can be maintained under highly active antiretroviral therapy (HAART). This study was designed to analyse whether HIV-specific responses in stable partially controlled patients during antiretroviral therapy (ART) differ from those observed in complete HAART failure and whether they contribute to the control of viral load (VL). METHODS: Three groups of patients were selected according to plasma HIV RNA levels during 18 months of ART: persistently low VL (LoVL; HIV RNA <10,000 copies/ml; n = 28), undetectable VL (UnVL; HIV RNA <200 copies/ml; n = 29) and high VL (HiVL; HIV RNA >10,000 copies/ml; n = 14). T-cell responses were studied using lymphoproliferative and interferon (IFN)-gamma-ELISpot assays against HIV-p24, -gp160, recall antigens, and 15 pools of HIV-(Gag + RT) peptides. RESULTS: Frequencies of IFN-gamma-producing CD4 T cells against HIV-p24 were higher in LoVL than in UnVL or HiVL groups [median, 131, 47 and 23 spot-forming cells (SFC)/1 x 10 peripheral blood mononuclear cells (PBMC), respectively; P = 0.012 and P = 0.047]. Lymphoproliferative responses to HIV-p24 and recall antigens were similar in LoVL and UnVL groups but lower in HiVL (P = 0.004). Frequencies of HIV-specific CD8 T cells were higher in LoVL than in UnVL (1340 versus 410 SFC/1 x 10 PBMC; P = 0.001). They correlated negatively with VL in the LoVL and HiVL (r, -0.393, P = 0.039 and r, -0.643, P = 0.024, respectively) and positively correlated with anti-HIV CD4 cell frequencies in the LoVL group only (r, 0.420; P = 0.026). CONCLUSION: Persistently low viral replication (<10,000 copies/ml) during ART stimulates high frequencies of HIV-specific CD4 and CD8 T cells compared to full virus suppression or complete ART failure. The association of high anti-HIV activity with large numbers of HIV-specific CD8 T cells contribute to the control of viral replication.     

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.     

Immune restoration disease in HIV-infected individuals receiving highly active antiretroviral therapy: clinical and immunological characteristics

BACKGROUND: HIV-infected patients responding to HAART can show a diverse spectrum of symptoms caused by inflammatory reaction. The pathogenesis of this phenomenon, called immune restoration disease (IRD), is unclear. This study describes the spectrum of IRD and analyses the immunological and clinical parameters that could be related to its development. METHODS: In a retrospective, matched case-control study, 17 HIV-infected individuals who developed inflammatory symptoms < 12 months after initiation of HAART were included. HIV-infected controls were matched for age, gender and CDC classification. Factors included in the analysis were: CD4+ and CD8+ cell counts, deltaCD4+ and deltaCD8+, CD4/CD8 ratios, HIV-1-RNA load (VL), AVL and the number of CDC events prior to HAART. RESULTS: The median time after initiation of HAART and developing IRD (n = 17) was 72 days (range 2-319). In nine cases (53%) a mycobacterial infection was identified as the underlying cause. HAART was started at a mean CD4+ count (+/- SD) of 55 x 10(6) /l (+/- 59) and 85 x 10(6) /l (+/- 78.0) for cases and controls, respectively (p = 0.13). After initiation of HAART, the CD4+ count showed a 10.6 fold increase at the onset of IRD in the cases and a 2.7 fold increase in the controls in an equal period of time (p = 0.020). The other parameters analysed did not differ significantly between cases and controls. CONCLUSION: We conclude that the risk of developing IRD is associated with a high-fold increase in CD4+ lymphocytes. In this study, mycobacteria are the pathogens most frequently associated with IRD.     

Thymic function in severely immunodeficient HIV type 1-infected patients receiving stable and effective antiretroviral therapy

The role of the thymus in long-term immune reconstitution has not been addressed in HIV patients who were severely immunodeficient prior to successful treatment with combination antiretroviral therapy (ART). Adult HIV-1 patients (n = 78) with nadir CD4+ T cell counts <100 T cells/microl, at least 12 months on ART and 6 months of complete viral suppression (<50 HIV RNA copies/ml) were selected from a patient database. The cohort was divided according to current CD4+ T cell counts and patients from the lowest (n = 15) and highest (n = 12) tertiles were studied. Thymic volume was assessed by spiral computed tomography. Naive (CD45RA+CD62L+) and replicating (Ki67+) T cells were quantitated by flow cytometry, T cell receptor excision circles (TREC) were assessed by real-time PCR, and serum IL-7 and testosterone by immunoassay. Patients with low CD4+ T cell counts had smaller thymuses [0(0-5.3) vs. 3.5(0-15.6) cm(3), p = 0.04] and were more likely to have no detectable thymus. They had similar proportions of replicating cells, but fewer naive CD4+ and CD8+ T cells and less TREC in CD4+ and CD8+ T cells/ml of blood than patients with high CD4+ T cell counts. However, some patients with no detectable thymus had high numbers of naive and TREC-bearing T cells. Thus, the recovery of CD4+ T cells in severely immunodeficient HIV patients with a virological response to ART is probably limited by thymic function. However, the data are consistent with extrathymic T cell production contributing to the naive T cell pool in some patients.     

Association of CD8+ T lymphocyte subsets with the most commonly used markers to monitor HIV type 1 infection in children treated with highly active antiretroviral therapy

In contrast to adults, there is no information about children concerning the effects of the new antiretroviral therapy on the chronic activation and expansion of CD8+ T cells. We have investigated the relationship between blood CD8(+) T cell subsets, with percent CD4+ cells (%CD4), percent CD8+ cells (%CD8), and plasma viral load (VL), in 39 vertically HIV-1-infected children receiving highly active antiretroviral therapy (HAART) (mean age, 7.6 years; range, 2-15.6 years). CD8+ subsets were examined by three-color multiparametric flow cytometry, and VL was quantified by standard assays. There was a strong positive correlation between activated CD8+ T cells and VL. An increase in memory and memory-activated CD8+ T cells correlated with increased VL, whereas nonactivated memory cells and CD28+ CD8+ T cells correlated negatively with VL. Naive and effector cells did not correlate with VL, although the CD8+ CD45RA -CD62L- subset correlated with increased VL. Activated CD8(+) T cells did not correlate with %CD4, but an increase in memory-activated and effector CD8+ T cells was associated with lower %CD4. Increased naive CD8+ and CD28 +CD8+ T cells showed a positive correlation with %CD4 and a negative correlation with %CD8. In conclusion, in HIV-1-infected children receiving HAART, the activation of CD8+ T cells is associated with high VL, whereas CD8 +CD28+ and nonactivated CD8+ memory cells are associated with lower viral load. Naive CD8+ and CD28 +CD8+ T cells are associated with an improved immunological status.     

Influence of prior antiretroviral experience on adherence and responses to new highly active antiretroviral therapy regimens

The impact of prior antiretroviral experience on adherence and clinical outcomes in patients initiating a new highly active antiretroviral therapy (HAART) regimen is not well defined. We performed an observational cohort analysis of antiretroviral-experienced or -naive HIV-infected patients prescribed a new HAART regimen (3538 patients) and enrolled in Kaiser Permanente Northern California from 1997 through 2002. Outcomes evaluated were HAART adherence and changes in HIV RNA level and CD4 T-cell counts over 12 and 24 months. The antiretroviral-naive group had a significantly greater odds of achieving >/=95% adherence to the HAART regimen over 12 months (adjusted odds ratio [OR] = 1.88, p < 0.001) and over 24 months (OR = 1.66, p < 0.001). The odds of achieving HIV RNA levels below limits of quantification also was higher among patients who were antiretroviral naive; over 24 months OR = 6.88, p < 0.001. Adjusted change in CD4 T-cell count was also greater among naive patients over 24 months (+67 cells/muL, p < 0.001), compared to antiretroviral-experienced patients. Years of antiretroviral experience did not affect adherence or any outcome measure. Adjusting for HAART adherence did not significantly affect HIV RNA results but did lessen CD4 T-cell count differences between antiretroviral-naive and -experienced patients. Thus, antiretroviral naive patients have improved HAART adherence, HIV RNA control, and CD4 T-cell count increases compared to antiretroviral-experienced patients regardless of years of antiretroviral experience. These findings should help direct HAART adherence efforts in HIV care clinics.     

CTLA-4 upregulation during HIV infection: association with anergy and possible target for therapeutic intervention

OBJECTIVE: To study the role of cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) during HIV infection. METHODS: Intracellular CTLA-4 expression, determined by flow-cytometry, and proliferative responses to HIV antigens, were studied in peripheral blood mononuclear cells (PBMC) from 93 HIV-1-infected [HIV(+)] patients and 40 HIV-1 seronegative controls. RESULTS: The proportions of CTLA-4 expressing CD4+ T cells were: (1) significantly higher in HIV(+) patients, 10.95 +/- 0.66%, than in controls, 6 +/- 0.45% (P < 0.0001); (2) inversely correlated to CD4+ counts (r = -0.67, P < 0.005, n = 16, drug-naive patients; r = -0.57, P < 0.0001, n = 77, HAART-treated patients); and (3) positively correlated to proportion of activated (HLA-DR+CD3+) (r = 0.53, P < 0.0001) and memory (CD45RO+CD4+) T cells (r = 0.46, P < 0.001). CD28 median fluorescence intensity in CTLA-4- cells was twice that in CTLA-4+ cells (140 +/- 5.3 versus 70 +/- 2.28, P < 0.00001), whereas cells low in CD28 and CD4, expressed more CTLA-4 (P < 0.0001). Higher proportion of CTLA-4+CD4+ cells expressed CCR5 and Ki-67, in comparison with CTLA-4-CD4+ cells, (65 +/- 11.9 and 25 +/- 7.5% versus 27 +/- 8.9 and 3.7 +/- 2%, P < 0.0001 and P < 0.01, respectively). Among HAART-treated patients, with viral load below detectable levels, CD4+ cells increase was inversely correlated to %CTLA-4+CD4+ cells (r = -0.5, P = 0.003, n = 39). Proliferation of PBMC to anti-CD3, gp-120 depleted HIV-1 antigen or HIV-1 p24 stimulation was inversely correlated with CTLA-4 levels (r = -0.68, P = 0.0035; r = -0.38,P = 0.04; and r = -0.43, P = 0.028, respectively). CONCLUSIONS: (1) CTLA-4 is upregulated during HIV infection and may therefore account for CD4 T-cell decline and anergy in HIV-1 infection. (2) Increased levels of CTLA-4 may undermine immune responses and in the HAART-treated patient-immune reconstitution. (3) Blocking of CTLA-4 may offer a novel approach for immune-based therapy in HIV infection.     

Interleukin-2 accelerates CD4 cell reconstitution in HIV-infected patients with severe immunosuppression despite highly active antiretroviral therapy: the ILSTIM study--ANRS 082

BACKGROUND: Despite effective highly active antiretroviral therapy (HAART), some patients infected with HIV have persistently low CD4 cell counts with risk of HIV disease progression. The addition of interleukin-2, a cytokine that stimulates CD4 T lymphocyte helper cells, may benefit patients with discordant responses. METHODS: A total of 72 HIV-infected patients with CD4 cell counts of 25-200 x 10(6) cells/l (median 145) and plasma HIV RNA < 1000 copies/ml were randomized in a multicentre study to receive open-label 4.5 x 10(6) IU interleukin-2 subcutaneously twice daily for 5 days every 6 weeks plus their ongoing HAART or were maintained on HAART alone (control group). After 24 weeks, all patients received interleukin-2 therapy plus HAART up to week 80. Primary end-point was the CD4 T cell area under the curve minus baseline up to week 24. RESULTS: After four cycles of interleukin-2, in an intent-to-treat analysis, the respective median CD4 cell area under the curve minus baseline values were +51 and +11 cells in the interleukin-2 (n = 34) and the control group (n = 36) (P < 0.0001). The percentage of patients in the two groups with CD4 cell counts > 200 x 10(6) cells/l was 81% and 33%, respectively (P < 0.0001). At week 80, the median CD4 cell counts in the two groups were 380 and 270 x 10(6) cells/l, respectively. Interleukin-2 treatment was reasonably well tolerated and did not result in sustained increases in plasma HIV RNA levels. CONCLUSIONS: Administration of interleukin-2 produces significant and sustained increase in CD4 cell counts in HAART-treated patients with persistent CD4 cell counts < 200 x 10(6) cells/l.     

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.     

300例艾滋病患者高效抗逆转录病毒治疗后免疫重建规律探讨

目的探讨高效抗逆转录病毒治疗（HAART）对中国南部地区艾滋病患者的免疫重建规律。方法收集近3年来300例患者的完整资料,按基线CD4^＋T细胞数分为A、B、C三组,观察基线及治疗1、3、6、12月末CD4^＋T淋巴细胞数、12月末血浆病毒载量（VL）、临床症状和毒副作用。结果抗病毒治疗12月末300例患者CD4^＋T淋巴细胞计数平均上升127个／1,以治疗3月后增长明显,3、12月末与基线CD4^＋T淋巴细胞计数比较差异有显著性（P〈0．05）;12月末273例（91％）患者血浆病毒载量（VL）〈5copies/ml,27例（9％）患者病毒载量（VL）〉50copies/ml,高病毒载量A组16例,C组4例;A组与C组比较差异有显著性（P〈0．05）;药物不良反应主要是外周神经炎（35．4％）、骨髓抑制（18．2％）、皮疹（15．2％）、肝功能损害（12．1％）、乳酸酸中毒（12．1％）和肾结石（6．1％）。结论HAART治疗对中国南部地区的艾滋病患者有效,能够实现免疫重建,但存在较多毒副作用。     

高效抗逆转录病毒治疗12个月后艾滋病患者的免疫重建观察

目的探讨高效抗逆转录病毒治疗（HAART）对AIDS患者的疗效及毒副作用。方法45例未经治疗的AIDS病人按基线CD4^＋T细胞计数分为两组,予12个月HAART,分别在基线及治疗1、3、6、9、12个月末随访血浆病毒载量（VL）、T细胞亚群和临床症状。结果抗病毒治疗12个月后45例病人血浆VL平均下降2．8lg拷贝／ml;CD4^＋细胞平均增长187个／μl,其中记忆表型增长119个／μl,纯真表型增长68个／μl,CD4^＋CD28^＋细胞比例显著升高;CD8^＋T激活亚群比例显著降低。基线CD4^＋T细胞计数〉100个／μl的14例病人治疗12个月后有10例血浆VL〈50拷贝／ml,而〈100个／μl的31例病人治疗后仅有11例血浆VL〈50拷贝／ml（P〈0．05）。出现血浆波动的病例数在两组也有统计学差异（分别为2例和14例,P〈0．05）。CD4^＋T细胞计数呈双相增长过程,其增量与血浆VL减少量呈显著正相关。常见的药物副作用有消化道反应、外周神经炎、肝功能损害等。结论HAART方案对AIDS病人有较好的疗效,能够实现免疫重建,但也存在较多毒副作用。     

Intracellular cytokines in the acute response to highly active antiretroviral therapy

OBJECTIVES: Successful highly active antiretroviral therapy (HAART) is usually associated with a rapid decline in HIV plasma RNA levels and a gradual increase in CD4 T cells. We examined whether changes in cytokine production and profile precede other immunological changes and whether these might occur in temporal association with plasma HIV RNA changes. DESIGN AND METHODS: Eleven HIV-1-infected patients were enrolled into a prospective cohort study; eight patients were naive to antiretroviral therapy. Blood samples were collected pre-therapy (week 0) and at 1, 2, and 3 weeks post-initiation of therapy. RESULTS: All 11 patients enrolled remained on triple HAART for 1 week, eight for 2 weeks, and six for > or = 3 weeks. When compared to week 0, these patients had a > or = 2-log10 decline in HIV plasma RNA levels and/or a decline to < or = 400 copies/ml by week 3 of therapy (p = 0.004). The numbers and percentages of CD4 and CD8 T cells, and the percentage of naive, memory, and activated T cells did not change significantly between weeks 0 and 1 or 0 and 3. Of all the immune parameters examined only: the percentage of CD4 T cells spontaneously producing tumor necrosis factor (TNF)-alpha (median, 2.4 versus 0.5% P = 0.025); the percentage of CD8 T cells spontaneously producing TNF-alpha (median, 0.6 versus 0.2% P = 0.037); and the percentage of CD3 T cells spontaneously producing interleukin-4 (median, 1.8 versus 0.8% P = 0.004) changed significantly between weeks 0 and 3. CONCLUSIONS: In these patients, decreases in the percentage of T cells spontaneously producing TNF-alpha or interleukin-4 preceded changes in CD4 T cells. If confirmed by others, these observations may be useful as early predictors of response to and early failure of HAART.     

Immune reconstitution and predictors of virologic failure in adolescents infected through risk behaviors and initiating HAART: week 60 results from the PACTG 381 cohort

The responses to HAART in HIV-infected adolescents infected through risk behaviors are not well defined. PACTG 381 collected intensive immunologic and virologic data on youth naive to or with minimal exposure to antiretroviral therapy who began HAART. Subjects were evaluated according to their weeks 16-24 virologic response. Comparisons with a cohort of HIV-uninfected adolescents from the REACH cohort were performed. Cox proportional hazards models were used to identify baseline and week 24 predictors of virologic failure. Only 69 of 120 subjects (58%) achieved virologic suppression by weeks 16-24, whereas 55 of 69 (80%) demonstrated control to week 60. Higher CD4+ naive T cells (CD4+/62L+/RA+: hazard ratio [HR], 2.13; p = 0.018), higher CD8+ activated T cells (CD8+/CD38+/DR+: HR, 1.40, p = 0.028 per 100 cells/mm3) and higher CD8+ naive T cells (CD8+/62L+/RA+: HR, 1.72; p = 0.005) at weeks 16-24 in subjects with early viral success were predictive of subsequent failure. By week 60, total CD4+ T cells remained significantly lower than in uninfected controls. Adolescents beginning HAART achieve moderate rates of viral suppression by weeks 16-24. In those who do achieve early virologic control, suppression to week 60 is high although total CD4+ T cells remain significantly lower than in uninfected controls. Several T cell markers were predictive of subsequent virologic failure in subjects achieving short-term success. Further study is warranted to determine whether these predictors provide any benefit to clinical management.     

Recovery of replication-competent virus from CD4 T cell reservoirs and change in coreceptor use in human immunodeficiency virus type 1-infected children responding to highly active antiretroviral therapy

Highly active antiretroviral therapy (HAART) suppresses plasma viremia in most patients with human immunodeficiency virus (HIV) infection. Prospective study of HIV-infected children (n=27) shows that, in 8 of 12 who responded to HAART (>/=0.5 log reduction in plasma HIV RNA), HAART restricted the number of coreceptors used by the predominant HIV isolate (mean number of coreceptors used at baseline was 4, vs. 1 coreceptor used at 6 months after treatment). This decrease was most striking in 6 of 8 children whose HIV coreceptor tropism changed from X4-tropic at baseline to R5-tropic. In 6 of 10 children tested, with plasma HIV RNA levels of <50 copies/mL, R5-tropic virus was isolated from CD4 T cell reservoirs. All the responding children had a significant increase in naive CD4 T cells (P<.05). These results show that persistent HIV T cell reservoirs are present in children and that HAART may influence the number and type of coreceptors used by the predominant virus isolate.     

Thymic involvement in immune recovery during antiretroviral treatment of HIV infection in adults; comparison of CT and sonographic findings

In adult HIV-infected patients, thymic size evaluated from CT scans seems to be important to the degree of immune reconstitution obtainable during treatment with highly active antiretroviral therapy (HAART). To examine whether ultrasound is as reliable as CT for estimating thymic size and predicting immune recovery, CT and ultrasound scans were performed in 25 adult HIV-infected patients and 10 controls. CD4 counts and naive CD4 counts were measured in order to determine immune reconstitution. Furthermore, the CD4+ T-cell receptor excision circle (TREC) frequency and T-cell receptor (TCR) repertoire were determined. The study demonstrated no correlation between the 2 scanning methods (r = 0.201, p = 0.358 in patients and r = 0.457, p = 0.184 in controls). Among the patients, no association was found between the sonographically estimated thymic size and immunological parameters such as CD4 count (r = 0.083, p = 0.706), naive CD4 count (r = 0.067, p = 0.762), CD4 + TREC frequency (r = 0.028, p = 0.900) and CD4 + TCR repertoire (r = -0.057, p = 0.828). These findings show that CT remains superior for assessing thymic size in adults and is preferable to ultrasound when evaluating the importance of a large thymus to immune recovery during HAART.     

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.