JAIDS Journal of Acquired Immune Deficiency Syndromes:
CD4+ T-Cell Immunodeficiency Is More Dependent on Immune Activation Than Viral Load in HIV-Infected Children on Highly Active Antiretroviral Therapy
Resino, Salvador PhD*; Seoane, Elena MD, PhD*; Gutiérrez, Maria Dolores Gurbindo MD, PhD†; León, Juan Antonio MD, PhD‡; Muñoz-Fernández, Maria Ángeles MD, PhD*
From the *Laboratorio de Inmuno-Biología Molecular; †Inmuno-Pediatría, Hospital General Universitario "Gregorio Marañón," Madrid; and ‡Pediatría-Infecciosas, Hospital Universitario "Virgen de Rocío," Sevilla, Spain.
Received for publication February 13, 2006; accepted March 31, 2006.
Supported by Fundación para la Investigación y la Prevención del SIDA en España, FIPSE (grant 12456/03), Fundación para la Investigación Sanitaria (FIS) del Ministerio de Sanidad y Consumo (PI040883, PI052479, PI052472, PI052411), Plan Nacional de Salud (SAF 2003-09209, SAF-2004-06778), Red Temática Cooperativa de investigación en SIDA (RIS G03/173) of FIS, and Red Temática Cooperativa de investigación en Genética (RIG C03/07) of FIS. Salvador Resino has staff researcher by FIS (CP04/00090) and Elena Seoane has staff researcher by FIS (CM04/00097).
Reprints: Salvador Resino, PhD, Hospital General Universitario "Gregorio Marañón," Laboratorio de Inmuno-Biología Molecular, C/ Doctor Esquerdo 46, 28007-Madrid, Spain. (e-mail: firstname.lastname@example.org).
Objective: The aim of this study was to analyze the association between CD4+ depletion and immune activation in HIV-1-infected children on highly active antiretroviral therapy (HAART).
Design and Setting: We carried out a cross-sectional study to determine the profile of several immunologic parameters in 143 children on HAART for more than 24 weeks. Children were stratified according to current immunologic status (CD4+ ≤15%, 15%-25%, and ≥25%) and viral load (VL) levels (<400 copies/mL; 400-10,000 copies/mL; and >10,000 copies/mL). We also studied 23 uninfected children as healthy controls.
Methods: Viral load (HIV-RNA copies per milliliter) was quantified using reverse transcriptase polymerase chain reaction molecular assay. T-cell subsets were determined by multiparametric flow cytometry.
Results: HIV-infected children with low percentage of CD4+ had high memory (CD45RO+) and low naive (CD45RA+) CD4+ and CD8+ T-cell values. Furthermore, children with CD4+ >25% had similar memory and naive CD4+ values as the healthy control group, whereas memory and naive CD8+ subsets were different from the healthy control values. In these HIV-infected children, when CD4+ was depleted, the amount of naive plus central memory CD8+ (CD28+CD57−) cells was decreased, whereas effector CD8+ (CD28−CD57+) cells were upregulated, and these values were always higher than healthy control values. Furthermore, children with low percentage of CD4+ showed significant upregulation of HLA-DR+CD38+ and HLA-DR+ in both CD4+ and CD8+ T-cells independent of VL levels.
Conclusions: Our data suggest that elevated immune activation could be responsible for CD4+ depletion rather than HIV replication because immunologic status is associated directly to immune activation and not to VL levels in HIV-infected children on HAART.
Human immunodeficiency virus type 1 (HIV-1) infection induces a severe CD4+ T-cell (CD4+) depletion, alterations in T-cells subsets, and a progressive impairment of the immune system.1,2 HIV infection also induces an increase in T-cell activation-associated cell surface markers such as CD38 and HLA-DR.3-5 These markers change in parallel with the progression of the HIV disease.3
In the classic model of AIDS pathogenesis, HIV infection is associated with a high rate of virus turnover and a short life span of virus-infected cells, and HIV-mediated killing of CD4+ is the central event in AIDS pathogenesis.6,7 An alternative theory is that chronic immune activation after HIV infection drives the progressive decline in CD4+ numbers and progression to AIDS.8-10 Thus, CD4+ depletion is related to virus-mediated death of infected CD4+ and apoptosis of uninfected "bystander" T-cells by activation-induced cell death. In a simian immunodeficiency virus-infected monkey model, viral infection induces minimal levels of immune activation and bystander immunopathology. However, this does not result in CD4+ depletion despite persistently high levels of virus replication, and they did not develop AIDS.11
The aim of this study was to analyze the association between CD4+ depletion and immune activation in HIV-1-infected children on highly active antiretroviral therapy (HAART).
One hundred forty-three vertically HIV-infected children were studied in a cross-sectional study. Inclusion criteria were (a) children on HAART with a protease inhibitor (PI) or nonnucleoside analogue HIV-1 reverse transcriptase inhibitor (NNRTI), (b) HAART for at least 24 weeks before the study, and (c) ≥5 years old.
Drugs were prescribed by the attending pediatrician according to the Centers for Disease Control and Prevention (CDC) guidelines.12 The study was conducted according to the Declaration of Helsinki and approved by the Ethical Committee of our hospital HGU "Gregorio Marañon." Clinical and immunologic classification was based on the 1994 revised guidelines of the CDC.13 We also studied 23 uninfected children as a healthy control group. The characteristics of the patients are shown in Table 1. We grouped children according to different immunologic degree of CD4+ depletion, immunologic status (CD4+ ≤15%, 15%-25%, and ≥25%) and virologic status [viral load (VL) <400 copies/mL; 400-10,000 copies/mL; and >10,000 copies/mL].
HIV-1 Infection Laboratory Markers
All infants were diagnosed as HIV-1-infected on the basis of positive results in both DNA polymerase chain reaction and virus culture assays.14 T lymphocytes in peripheral blood were quantified by flow cytometry (FACScan, Becton-Dickinson Immunocytometry Systems, San Jose, CA),14 and VL was measured in 200 μL of plasma using a quantitative assay (Amplicor monitor, Roche Diagnostic Systems, Brandenburg, NJ).14
Quantification of CD4+ or CD8+ T-Cell Subsets
The monoclonal antibodies used for the analysis of T-cell subsets were conjugated with fluorescein isothyocyanate (anti-IgG1, anti-HLA-DR, anti-CD45RA, anti-CD38, and anti-CD57), phycoerytherin (anti-IgG1, anti-CD45RO, anti-CD62L, anti-CD28, and anti-HLA-DR), and peridinin chlorophyll protein (anti-CD4 and anti-CD8). The monoclonal antibodies were obtained from Becton-Dickinson Immunocytometry Systems, except anti-CD38 (Immunotech, Marseilles, France). T-cell subsets were analyzed by 3-color multiparametric flow cytometry in total blood that had been lysed and washed.15 Naive T-cells were defined as cells with bright expression of CD45RA and positive for CD62L (CD45RAhi+CD62L+).15 Memory T-cells were defined as CD45RO+. Activated T-cells were defined as HLA-DR+, CD38+, and HLA-DR+CD38+. Memory-activated T-cells were defined as CD4+CD45RO+HLA-DR+ or CD8+CD45RO+CD38+. Naive plus central memory CD8+ cells were defined as CD8+CD28+CD57−, pre-effectors were defined as CD8+CD28−CD57−, and effectors were defined as CD8+CD28−CD57+. Acquisition was performed in a FACScan (Becton-Dickinson Immunocytometry Systems) cytometer using the Lysis II software (Becton-Dickinson) within 2 hours of cell staining as previously described.15 Data were analyzed using Lysis II analysis program (Becton-Dickinson). Appropriate isotypic controls (IgG1-FITC, IgG1-PE) were used to evaluate the nonspecific staining, which was deducted from the remaining results. We measured HLA-DR and CD38 relative fluorescence intensities as the mean of fluorescence intensities (MFI) using single-parameter histograms with no cursor sets.
We stratified HIV-infected children into groups, according to the degree of CD4+ depletion or current immunologic status (CD4+ ≤15%; 15%-25%, and ≥25%) and VL levels (VL <400 copies/mL; 400-10,000 copies/mL; and >10,000 copies/mL) (Table 1).
First, we analyzed the relationship between the percentage of T-cell subsets and percentage of CD4+ inside of each VL strata using the Pearson correlation coefficient. This analysis was carried out inside each current immunologic status or inside each VL level separately. Values for both range between −1 (a perfect negative relationship) and +1 (a perfect positive relationship). A value of 0 indicates no linear relationship.
Next, we carried out a crossed analysis for the differences among groups of current immunologic status or VL levels. Differences in immunologic markers among groups of children were analyzed using 1-way analysis of variance or H-Kruskal-Wallis according to sample size. Next, a nonparametric test (Mann-Whitney U test) was used. All P values were 2-tailed, and the threshold of significance was set at 0.05.
At the entry of study, all children were more than 5 years old, and they were on HAART for at least 24 weeks before the study. At the entry of study, HAART included a median of 2 (min; max: 0; 3) nucleoside analogue HIV reverse transcriptase inhibitor (NRTI), 1 (0; 3) PI, and 0 (0; 1) NNRTI. Inside each current immunologic status, children with VL <400 copies/mL; 400 to 10,000 copies/mL; and >10,000 copies/mL had similar age values and CD4+ or CD8+ percentages (Table 1).
Relationship Between the Percentage of T-Cell Subsets and Percentage of CD4+
We analyzed the correlation between the percentage of T-cell subsets and percentage of CD4+ inside each VL level group (VL <400 copies/mL; 400-10,000 copies/mL; and >10,000 copies/mL) (Table 2). Overall, we found a positive correlation of CD4+ with naive (CD45RAhi+CD62L+) T-cells and CD4+CD38+ cells (most of them naive cells). Conversely, a negative correlation of CD4+ with memory (CD45RO+) T-cells, activated (HLA-DR+, HLA-DR+CD38+) T-cells, and effector CD8+CD28−CD57+ T-cells were found. We also found a negative correlation between CD4+ and the level of HLA-DR expressed on T-cell surface measured as MFI.
T-Cell Subsets According to Immunologic Status Inside Each VL Group
We found in HIV infection an imbalance in naive/memory-effector distribution. HIV-infected children with low percentage of CD4+ had high values of memory (CD45RO+) and low values of naive (CD45RAhi+CD62L+) CD4+ or CD8+ (Fig. 1A, B). Furthermore, HIV-infected children with CD4+ >25% had similar values of memory and naive CD4+ as healthy controls, whereas memory and naive CD8+ values were different from healthy control group values (Fig. 1A, B).
We found an evident relationship between CD8+ expansion and low percentage of CD4+. Therefore, children with low percentage of CD4+ had diminished values of naive plus central memory CD8+ cells (CD8+CD28+CD57−), and these values were always lower than healthy control values. On the other hand, effector CD8+ (CD8+CD28−CD57+) and pre-effectors (CD8+CD28−CD57−) were upregulated in HIV-infected children with low percentage of CD4+, and these values were always higher than healthy control values (Fig. 2).
In HIV-infected children, an elevated proportion of T-cells (CD4+ or CD8+) that express CD38 and HLA-DR was directly associated with low percentage of CD4+ (Fig. 3A, B). Furthermore, we found elevated values of memory-activated T-cells (CD4+CD45RO+HLA-DR+ and CD8+CD45RO+CD38+) (Fig. 3A, B) in HIV-infected children with low percentage of CD4+. However, we found a different pattern of CD38 expression on T-cells (CD4+ or CD8+) (Figs. 4C and 2D). CD4+CD38+ percentage and MFI values were associated with high CD4+ values in children with VL <400 copies/mL. Furthermore, CD8+CD38+ values were not associated with low percentage of CD4+ (Table 2).
The most significant finding of the study was that independent of VL levels, chronically HIV-infected patients on HAART had persistently high expression of T-cell activation markers when their CD4+ values were low. We grouped the children in stratum of VL levels: VL <400 copies/mL could be considered as undetectable VL; the range of 400 to 10,000 copies/mL represents children on HAART who have some oscillations of VL during their HIV disease; and the range >10,000 copies/mL represents children who have wrong control of VL. Overall, inside each group of VL, HIV-infected children with the lowest percentage of CD4+ had the highest values of memory and activated CD4+ and CD8+ T-cells, and effector CD8+. At the same time, they had the lowest values of naive CD4+ and CD8+ T-cells and central memory CD8+.
The rates of cell death are in vivo increased in T-cells.16,17 Specifically, 30% to 60% of memory CD4+ are infected by simian immunodeficiency virus at the peak of infection, and most of these infected cells disappear within 4 days.18 However, during HIV chronic infection, other mechanisms could have an important role in CD4+ depletion.16,17 Direct killing of uninfected cells by HIV could be related to the chronic high level of T-cell activation that is induced by continuous HIV replication.19 Therefore, HIV-induced chronic immune activation is involved in the loss of CD4+ in HIV-infected patients, and the rate of CD4+ depletion correlates more with markers of immune activation than with VL. On the other hand, VL predicts the rate of CD4+ depletion, which could also be explained by a process wherein the level of viral replication either determines or reflects the prevailing level of T-cell activation, and thus only indirectly affects the CD4+ count.20
A mechanism of CD4+ depletion is the failure of T-cell production by the thymus of HIV-infected children. It is well established that HIV infection adversely affects the thymus in both children and adults.21 Yet the consequences of this thymic inhibition are worse in children, and this has been proposed as one cause of the rapid progression of the disease in them.22-24 In this study, HIV-infected children with low percentage of CD4+ had lower percentages of naive CD4+ and CD8+ than children with CD4+ >25%, when grouped by VL levels. Moreover, when we stratified all children according to immunologic status, we did not find association among VL and naive CD4+ or CD8+ cells (data not shown). However, when we stratified all children according to VL levels, we found a strong negative association among CD4+ and memory and activated T-cells in each VL strata. This fact apparently contradicts the previous data in HIV-infected children that indicated an inverse association between VL and thymic function.25,26 Our results indicate that naive T-cell depletion could be likely due to immune activation status rather than HIV replication.
Our results could explain the so-called immunologically discordant response to HAART, in which there is low percentage of CD4+ but undetectable VL. These patients maintain a high level of T-cell activation when compared with patients with both virologic and immunologic responses.27 However, virologically discordant patients with significant increases in their CD4+ counts despite incomplete viral suppression display decreased levels of immune activation.28 Moreover, our patients who optimally suppress viral replication showed high levels of T-cell activation when their percentages of CD4+ were low. This finding could contradict other studies that indicate a marked reduction in expression of T-cell activation markers as viral load is suppressed,28,29 but the Deeks and Hellerstein study28 showed T-cell activation decreases in patients failing therapy but who exhibit CD4+ reconstitution. Therefore, T-cell activation and CD4+ depletion seem to have a positive association, and T-cell activation could be a decisive factor in depletion and recovery of CD4+.
The similar association between CD4+ depletion and immune activation in each VL group supports the hypothesis that immune activation rather than viral replication could lead to the destruction and depletion of CD4+.10 The generalized immune activation not only provides a suitable target for viral replication but also may change T-cell subset homeostasis, and it is also probable that a strong immune activation can contribute to CD4+ depletion.8,15 In fact, the generation of activated CD4+ (T-cells preferentially infected by HIV) provides a fertile substrate for viral replication, thus creating the conditions for a vicious cycle in which more viral replication induces more immune activation, which in turn allows more viral replication, and so on.30 This immune activation may drive the progression of HIV disease by disrupting the homeostatic equilibrium of resting cell populations.30 Moreover, the burst of T-cell proliferation occurs continuously by stimulation of proinflammatory factors and antigens, and it causes the switch of resting to effector CD8+. In our work, we did not find an association between VL and percentage of CD8+CD28−CD57+, but we found a positive association between percentage of CD4+ and effector CD8+ inside each VL strata.
The CD38 molecule is expressed in immature lymphocytes,31 but is also induced after an acute active viral infection.32 In children, CD4+CD38+ is a marker of immaturity that is expressed in cells with a naive phenotype.3 This way, we found positive association between CD4+ and CD4+CD38+. By contrast, CD8+CD38+ is associated with a worse prognosis, a decline of CD4+ and an increase in VL.29,33 In this study, only HIV-infected children with CD4+ <15% had a slight increase in frequency of activated CD8+, but not in CD4+, when VL was high (data not shown). Therefore, the effect of HIV replication was only evident in HIV-infected children with severe immunodeficiency because they had an elevated immune activation.3,8 These findings would support assessing the expression of CD38 as a prognostic marker to monitor the response to HAART.29,34
Our study has several limitations: (a) The study used percentage of CD4+ as a parameter for CD4+ T-cell depletion. However, the number of CD8+ T-cells, which increases by inflammation, influences the percentage of CD4+. Thus, the association between CD4+ depression (low percentage of CD4+) and the levels of activation may be overly detected. However, we could not carry out this analysis because the groups of children with CD4+ <200 were too small to validate the statistical analysis. (b) The interpretation of the association of CD4+ depletion with T-cell phenotypes and VL may be more complicated when patients are on treatment. The source of immune activation in the patients with undetectable plasma viremia is unknown. It might be a result of residual viral replication within the tissues, drug side effects, or even a secondary response to immune reconstitution. In addition, protease inhibitor may have some inhibitory effect on apoptotic process and thus increase CD4+ count.
In this study, we report that HIV-infected children on HAART with different VL levels having similar degrees of CD4+ depletion showed approximately similar levels of immune activation and imbalance of naive, memory, and effector T-cells. In summary, our data suggest that elevated immune activation could be responsible for CD4+ depletion rather than HIV replication because immunologic status is associated directly to immune activation and not to VL levels in HIV-infected children on HAART.
We thank Jose Maria Bellón Cano and Alejandro Alvaro-Meca for their statistical assistance and Nicholas Weber for his language corrections.
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