JAC Advance Access originally published online on February 16, 2006
Journal of Antimicrobial Chemotherapy 2006 57(4):798-800; doi:10.1093/jac/dkl032
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Correspondence |
Interleukin-7 levels before highly active antiretroviral therapy may predict CD4+ T-cell recovery and virological failure in HIV-infected children
1 Laboratorio de Immunobiología Molecular of Hospital ‘Gregorio Marañón’, Madrid, Spain; 2 Servicio de Pediatría-Infecciosas of Hospital ‘Virgen del Rocío’, Sevilla, Spain; 3 Servicio de Inmuno-Pediatría of Hospital ‘Gregorio Marañón’, Madrid, Spain
* Corresponding author. Tel: +34-91-5868565; Fax: +34-91-586-8018; E-mail: sresino.hgugm{at}salud.madrid.org
Keywords: cytokines , protease inhibitors , HAART , prognostic markers , reconstitution
Sir,
Highly active antiretroviral therapy (HAART) in HIV-infected children leads to an increase in the number of naive CD4+ T-cells (CD4+)1 that correlates with an increase in thymus volume2 and neolymphopoiesis.3 Nevertheless, the factors involved in the regeneration of T-cells through thymic-dependent mechanisms in HIV-infected children under HAART are still unknown and might be of relevance in the monitoring of HIV infection. One of the candidates to play a key role in this process is interleukin-7 (IL-7), which promotes thymic differentiation.4 In addition, IL-7 enhances T-cell proliferation in T-cell-depleted individuals, but not under normal conditions.5 Interestingly, HIV-infected patients have abnormally high plasma IL-7 levels associated with low numbers of CD4+.1
In order to establish the prognostic value of plasma IL-7 levels before HAART (baseline) we carried out a retrospective longitudinal study in 27 HIV-infected children on HAART. The inclusion criteria were as follows: (i) to begin HAART with protease inhibitor, (ii) CD4+ 
500 cells/mm3 (%CD4+ 20%) at entry to the study, (iii) at least 6 months of follow-up and (iv) age more than 1 year. The baseline values were obtained during the last doctor's visit prior to HAART implementation. Children were divided into two groups according to their percentile 75 (P75) of plasma IL-7 at baseline: (i) low IL-7 group: 21 children on HAART with IL-7 P75 (11.97 pg/mL) at baseline [median: 7.5 (range 1.3–11.9) pg/mL] and (ii) high IL-7 group: 6 children on HAART with IL-7 > P75 (11.97 pg/mL) at baseline [median: 20.8 (range 12.9–29.8) pg/mL]. HIV-infected children were compared with an age-matched control group (n = 26), with IL-7 median = 0.4 pg/mL (range 0.2–1.5). Viral load (VL), T-cell subsets, plasma IL-7 and TCR rearrangement excision circles (TRECs) were measured every 3 months for all patients.1 Thymic function was studied by quantifying TREC production in PBMC by real-time quantitative PCR (LightCycler system; Roche Molecular Biochemicals, Mannheim, Germany).1 Quantification of plasma IL-7 levels was carried out using an ELISA assay (Quantikine HS IL-7 kit; R&D Systems, Abingdon, UK).1 The Mann–Whitney U-test was applied for quantitative variables. We performed the survival analysis according to the P75 = 11.97 pg/mL of plasma IL-7 levels at baseline to determine the time to achieve CD4+ 
25% or undetectable VL (outcome variables). Cox regression analyses were performed to assess the relative proportion (RP) of the appearance of CD4+ 25% in the high IL-7 group relative to the low IL-7 group.
Children with IL-7 11.97 pg/mL had higher TREC values than children with IL-7 > 11.97 pg/mL (P < 0.05), but both HIV groups had much lower TREC values than controls (P < 0.05). However, there were no statistical differences in other clinical, immunological and virological characteristics, or antiretroviral regimens per group at baseline, among the HIV-infected children (the two groups were comparable at baseline). During the whole follow-up period, no child progressed to AIDS or death.
Children with IL-7 > 11.97 pg/mL achieved CD4+ 25% faster than children with IL-7 11.97 pg/mL (10.6 ± 6.4 months versus 37.1 ± 16.5 months; P = 0.017) (Figure 1). Children with IL-7 > 11.97 pg/mL had an RP to achieve CD4+ 25% during follow-up of 3.24 (95% CI: 1.16; 9.0). However, children with IL-7 > 11.97 pg/mL achieved VL 400 copies/mL in shorter time than children with IL-7 11.97 pg/mL (35.9 ± 22.8 months versus 7.4 ± 3.2 months; P = 0.057) (Figure 1). Children with IL-7 11.97 pg/mL had an RP to achieve VL 400 copies/mL of 3.92 (95% CI: 1.15; 13.4).
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In this study, we show that HIV-infected children with lower plasma IL-7 levels (<11.97 pg/mL) pre-HAART have a slower recovery of CD4+ counts after HAART. Thus, plasma IL-7 levels could be a prognostic marker of CD4+ recovery in HIV-infected children under HAART. In contrast, we did not find a prognostic value for TRECs and CD4+ count at baseline (data not shown). This could be owing to the enhanced proliferation under uncontrolled VL at baseline, since any changes in the T-cell pool during HIV-1 infection, measured by TREC concentration, could be most likely related to an increased activation and proliferation of T-cells, leading to the dilution of TRECs.
Previous studies in HIV-infected adults with low plasma IL-7 levels showed a slow recovery of naive CD4+ counts after HAART,6 which correlated with thymus atrophy observed in adult patients.7 Leal et al. suggested that high IL-7 levels produced in response to T-cell depletion at baseline might activate thymic rebound in HIV-patients under HAART.7 Plasma IL-7 levels may reflect the functional capacity of the lymphoid organs to restore the depleted CD4+7 both in generation of naive T-cells in the thymus and in T-cell pool expansion in peripheral lymphoid tissues.5 This is because an increase in peripheral IL-7 production occurs under HIV-1-mediated T-cell depletion, stimulating T-cell differentiation, survival and/or expansion.8
In our study, all HIV-infected children had very low CD4+ counts at baseline, which corresponded with much higher IL-7 levels than those of the control group. This fact was in agreement with the works of Napolitano et al.8 and Fry et al.9 who demonstrated a strong inverse correlation between high plasma IL-7 levels and low CD4+ counts in HIV-infected patients.
However, HIV infection could decrease the production of IL-7. Therefore, although some children may have low CD4+ levels they would not produce enough IL-7 to stimulate the T-cell recovery. In this regard, the group with IL-7 < 11.97 pg/mL levels had a substantially greater proportion of children with AIDS (76%, 16/21) than the group with IL-7 11.97 pg/mL (33%, 2/6). This fact per se may have an important influence on the CD4+ response to HAART. However, we did not find an association between AIDS and CD4+ recovery.
It has been reported that IL-7 induces stimulation and differentiation of primary human T-cells and thymocytes and hence may induce expression of latent HIV.10 Thus, IL-7 response to T-cell depletion may enhance T-cell production, but at the same time may foster HIV-1 disease progression, allowing for the emergence of more virulent HIV-1 strains characterized by syncytium-inducing isolate capability and rapid replication rate in HIV-infected children.11,12 In our study, we found that children with IL-7 > 11.97 pg/mL had worse VL control during the follow-up.
Our study has several limitations as it was carried out in a small size paediatric population with moderate/severe immunodeficiency and high VL.
In conclusion, we showed that IL-7 levels pre-HAART might have a dual functionality as a prognostic marker in HIV-infected children: high IL-7 is a good predictor of both CD4+ recovery and virological failure in HIV-infected children on HAART.
Transparency declarations
The authors do not have commercial or any other associations that might pose a conflict of interest.
Acknowledgements
We wish to thank José María Bellón (Hospital Gregorio Marañón) for the excellent statistical assistance. Sources of financial support: 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. S. R. has staff researcher funding from FIS (CP04/00090).
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