Low thymic output, peripheral homeostasis deregulation, and hastened regulatory T cells differentiation in children with 22q11.2 deletion syndrome.

OBJECTIVE: To perform an extensive analysis of the immune status of asymptomatic children with the 22q11.2 deletion syndrome, with special emphasis on the regulatory T cells (Treg) population. STUDY DESIGN: Analysis of thymic function, frequency and absolute counts of immune subsets, and phenotype of Treg were performed in 10 asymptomatic children bearing the 22q11.2 deletion and compared with 12 age-matched, healthy children. RESULTS: Children with 22q11.2 deletion syndrome showed a curtailed thymic output, lower T-cell levels, and a homeostatic deregulation in the CD4 T-cell compartment, characterized by a greater proliferative history in the naïve CD4 T-cell subset. Treg numbers were markedly reduced in children with 22q11.2 deletion syndrome, and remaining Treg showed mostly an activated phenotype. CONCLUSIONS: Reduced thymic output in children with 22q11.2 deletion syndrome could be related with an increased proliferation in the naïve CD4 T-cell compartment and the consequent Treg activation to ensure that T-cell expansion remains under control. Deregulated peripheral homeostasis and loss of suppressive capacity by Treg could compromise the integrity of T-cell immunity during adulthood and play a relevant role in the increased incidence of autoimmune diseases reported in patients with the 22q11.2 deletion syndrome.

Rate of candidiasis among HIV-infected children in Spain in the era of highly active antiretroviral therapy (1997-2008).

BACKGROUND: Candidiasis is the most common opportunistic infection seen in human immunodeficiency virus (HIV)-infected individuals. The aim of our study was to estimate the candidiasis rate and evaluate its trend in HIV-infected children in Spain during the era of highly active antiretroviral therapy (HAART) compared to HIV-uninfected children. METHODS: We carried out a retrospective study. Data were obtained from the records of the Minimum Basic Data Set from hospitals in Spain. All HIV-infected children were under 17 years of age, and a group of HIV-uninfected children with hospital admissions matching the study group by gender and age were randomly selected. The follow-up period (1997-2008) was divided into three calendar periods: a) From 1997 to 1999 for early-period HAART; b) from 2000 to 2002 for mid-period HAART; and c) from 2003 to 2008 for late-period HAART. RESULTS: Among children with hospital admissions, HIV-infected children had much higher values than HIV-uninfected children during each of the three calendar periods for overall candidiasis rates (150.0 versus 6.1 events per 1,000 child hospital admissions/year (p < 0.001), 90.3 versus 3.1 (p < 0.001), and 79.3 versus 10.7 (p < 0.001), respectively) and for non-invasive Candida mycosis (ICM) rates (118.5 versus 3.8 (p < 0.001), 85.3 versus 2.3 (p < 0.001), and 80.6 versus 6.0 (p < 0.001), respectively). In addition, HIV-infected children also had higher values of ICM rates than HIV-uninfected children, except during the last calendar period when no significant difference was found (32.4 versus 1.2 (p < 0.001), 11.6 versus 0.4 (p < 0.001), and 4.6 versus 2.3 (p = 0.387), respectively). For all children living with HIV/AIDS, the overall candidiasis rate (events per 1,000 HIV-infected children/year) decreased from 1997-1999 to 2000-2002 (18.8 to 10.6; p < 0.001) and from 2000-2002 to 2003-2008 (10.6 to 5.7; p = 0.060). Within each category of candidiasis, both non-ICM and ICM rates experienced significant decreases from 1997-1999 to 2003-2008 (15.9 to 5.7 (p < 0.001) and 4.1 to 0.3 (p < 0.001), respectively). CONCLUSIONS: Although the candidiasis rate still remains higher than in the general population (from 1997 to 2008), candidiasis diagnoses have decreased among HIV-infected children throughout the HAART era, and it has ceased to be a major health problem among children with HIV infection.

Preterm neonates show marked leukopenia and lymphopenia that are associated with increased regulatory T-cell values and diminished IL-7.

INTRODUCTION: Current advances in neonatology have improved survival among preterm and low-birth-weight infants. However, the risk of neonatal death in preterm infants is much greater than in full-term neonates and is frequently associated with infections. METHODS: Little is known about the immune status of preterm neonates; therefore, we analyzed the frequency and absolute counts of different immune populations in 211 cord blood samples taken from very-preterm to full-term neonates. RESULTS: We found that absolute counts of all the immune subsets analyzed (i.e., monocytes, granulocytes, B cells, natural killer (NK) cells, CD4(+), and CD8(+) T cells) were markedly lower in preterm infants than in full-term infants. Surprisingly, we observed that regulatory T cells (Tregs) were the only cell subset that did not decrease in preterm infants, and their frequency was even higher than in full-term infants. DISCUSSION: Tregs are crucial to maternal-fetal tolerance, but their suppressive role could be also implicated in the leukopenia observed in preterm infants. We did not observe differences in thymic function, but we found that plasma levels of interleukin (IL)-7 and the frequency of its receptor were significantly decreased in preterm infants. Our results could help to identify leukopenia and to implement immune therapies that significantly diminish mortality in preterm neonates.

A leaky mutation in CD3D differentially affects αß and γδ T cells and leads to a Tαß-Tγδ+B+NK+ human SCID.

T cells recognize antigens via their cell surface TCR and are classified as either αß or γδ depending on the variable chains in their TCR, α and ß or γ and δ, respectively. Both αß and γδ TCRs also contain several invariant chains, including CD3δ, which support surface TCR expression and transduce the TCR signal. Mutations in variable chains would be expected to affect a single T cell lineage, while mutations in the invariant chains would affect all T cells. Consistent with this, all CD3δ-deficient patients described to date showed a complete block in T cell development. However, CD3δ-KO mice have an αß T cell-specific defect. Here, we report 2 unrelated cases of SCID with a selective block in αß but not in γδ T cell development, associated with a new splicing mutation in the CD3D gene. The patients' T cells showed reduced CD3D transcripts, CD3δ proteins, surface TCR, and early TCR signaling. Their lymph nodes showed severe T cell depletion, recent thymus emigrants in peripheral blood were strongly decreased, and the scant αß T cells were oligoclonal. T cell-dependent B cell functions were also impaired, despite the presence of normal B cell numbers. Strikingly, despite the specific loss of αß T cells, surface TCR expression was more reduced in γδ than in αß T cells. Analysis of individuals with this CD3D mutation thus demonstrates the contrasting CD3δ requirements for αß versus γδ T cell development and TCR expression in humans and highlights the diagnostic and clinical relevance of studying both TCR isotypes when a T cell defect is suspected.

Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome.

Several syndromes manifest as recurrent daily fevers, skin lesions, and multisystem inflammation. We describe 4 patients with early-onset recurrent fevers, annular violaceous plaques, persistent violaceous eyelid swelling, low weight and height, lipodystrophy, hepatomegaly, and a range of visceral inflammatory manifestations. Laboratory abnormalities included chronic anemia, elevated acute-phase reactants, and raised liver enzymes. Histopathologic examination of lesional skin showed atypical mononuclear infiltrates of myeloid lineage and mature neutrophils. Our patients have a distinctive early-onset, chronic inflammatory condition with atypical or immature myeloid infiltrates in the skin. We propose the acronym CANDLE (chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature) syndrome for this newly described disorder, which is probably genetic in origin.

Slow progression of human immunodeficiency virus and hepatitis C virus disease in a cohort of coinfected children.

We carried out a retrospective study to determine the evolution of 23 vertically HIV-1/HCV coinfected children and 30 vertically HIV-1 infected children (control group). Six out of 23 HIV-1/HCV coinfected children developed AIDS versus 20 out of 30 HIV-1 children (P < 0.05). HIV-1/HCV children had a good evolution in relation to CD4 and HIV-RNA viral load. They presented higher CD8 counts than HIV-1 children during long periods, and slower progression of HCV liver disease.

Positive virological outcome after lopinavir/ritonavir salvage therapy in protease inhibitor-experienced HIV-1-infected children: a prospective cohort study.

BACKGROUND: Lopinavir/ritonavir has demonstrated antiviral activity in the HIV-infected patient. OBJECTIVE: To analyse virological response to lopinavir/ritonavir therapy in previously protease inhibitor (PI)-experienced HIV-1-infected children. MATERIALS AND METHODS: Sixty-seven HIV-1-children on lopinavir/ritonavir were studied in a multicentre prospective cohort observational study. The outcome variables were undetectable viral load (uVL; VL < or =400 copies/mL) and virological failure after uVL with a rebound of VL >400 copies/mL. VL and genotype of HIV-1-isolates were measured using standard assays. RESULTS: 83.5% of children had a 1 log10 VL decrease including 65.6% who reached uVL. Children with >2 changes of antiretroviral therapy (ART) or >5 drugs needed a median time of 3-4 months higher than children with < or =2 changes of ART or < or =5 drugs previous to lopinavir/ritonavir, to reach those values, and the relative proportions (RP) were 2.2 (P =0.038) and 1.9 (P=0.050), respectively. Children with CD4+>15% (P=0.122), VL < or =30,000 (P < 0.001) copies/mL, and age >12 years (P=0.096) achieved an earlier control of VL during the follow-up. The children with virological failure or rebound of VL had higher baseline VL and lower CD4+ T-lymphocytes/mm3 and had taken a greater number of drugs previous to lopinavir/ritonavir. HIV-children with a new nucleoside reverse transcriptase inhibitor (NRTI), or protease inhibitor (PI) or PI plus non-nucleoside reverse transcriptase inhibitors (NNRTI) in the current regimen had a better virological response than children without these new drugs. Also, children with <6 protease mutations had an RP of 2.31 of achieving uVL. CONCLUSIONS: Highly active antiretroviral therapy (HAART) including lopinavir/ritonavir induces beneficial effects in terms of virological outcome responses, and it is an effective option for salvage therapy in PI-experienced HIV-1-infected children.

The effects on infants of potent antiretroviral therapy during pregnancy: a report from Spain.

BACKGROUND: The purpose of our study was to assess the effects on infants of protease inhibitor (PI)-based antiretroviral therapy (ART) given to their HIV-positive mothers during pregnancy. MATERIAL/METHODS: A multicenter observational study was carried out at 11 centers in Spain, involving 124 HIV-1-infected pregnant women under ART and their infants. The mothers were classified according to the ART protocols used during pregnancy into two groups: group A, 52 women with > or =2 nucleoside reverse transcriptase inhibitors (NRTI) with or without NNRTI, for a mean time of 4.7+/-2.2 months; and group B, 72 women on protease inhibitor (PI)-based regimens for 5.4+/-2.6 months. RESULTS: Maternal therapy was well tolerated, with no serious adverse effects on pregnancy course. No newborn was infected with HIV-1. There were two deaths at birth (group B), both with extreme prematurity. Among the 126 ART-exposed infants (4 siblings), the most common toxicity was anemia (29%), without significant differences between the two groups. Low birthweight and prematurity were also common (21% and 14%, respectively). CONCLUSIONS: Optimal management of HIV-1 infection in women, regardless of their pregnancy status, can be recommended in more developed countries, without adverse effects on pregnancy outcome, and dramatically decreasing vertical transmission. HAART with PI versus potent ART during pregnancy was effective and safe for infants throughout the 12-month follow-up. In the light of recent advances in anti-HIV-1 pregnancy therapy, the long-term safety of these prophylactic and therapeutical strategies should be studied.

Neuroprotective effects of early antiretrovirals in vertical HIV infection.

We performed a retrospective study of a series of 58 of 189 vertically HIV-1 infected children who went on to develop progressive HIV-1-associated encephalopathy to assess real-life effects of early antiretroviral therapy on neurologic outcome. Our findings clearly indicate that antiretroviral therapy before the onset of neurologic symptoms delayed presentation of progressive HIV-1-associated encephalopathy, with an additional beneficial effect on survival.

Viral load and CD4+ T lymphocyte response to highly active antiretroviral therapy in human immunodeficiency virus type 1-infected children: an observational study.

An observational study was performed involving 95 children with vertically transmitted human immunodeficiency virus type 1 infection to assess the sustainability of undetectable viral loads (VLs) and increased CD4+ T lymphocyte percentages after 48 months of highly active antiretroviral therapy (HAART). The median time to achieve a 10% increase in the CD4+ T lymphocyte percentage was 11.01 months. The median time to achieve an undetectable VL was 6.4 months. At the end of the study, 64.2% of the children had achieved an undetectable VL. Of the patients with an initial VL of >3.6 log10 copies/mL, 74.7% had a decrease in the VL of 1 log10 copies/mL. By contrast, of the patients who presented with an initial VL of >4.6 log10 copies/mL, 37.9% had a decrease of >2 log10 copies/mL. Higher VL at baseline, antiretroviral therapy regimens received before HAART, and multiple drug switches while receiving antiretroviral therapy were all inversely associated with an undetectable VL. A CD4+ T lymphocyte percentage of >25% was directly associated with undetectable VL during the follow-up period. In conclusion, first-line HAART induces beneficial virological and immunological outcome responses in children.

Low blood CD8+ T-lymphocytes and high circulating monocytes are predictors of HIV-1-associated progressive encephalopathy in children.

OBJECTIVE: Human immunodeficiency virus type 1 (HIV-1)-associated progressive encephalopathy (PE) is a common and devastating complication of HIV-1 infection in children, whose risk factors have not yet been clearly defined. Regardless of the age of presentation, PE shortens life expectancy. Paradoxically, as survival of patients has been prolonged as a result of the use of antiretroviral therapy, the prevalence of PE has increased. Therefore, a predictive marker of PE emergence is critical. The objective of this study was to determine in an observational study whether any immunologic (CD4(+) and CD8(+) T-lymphocyte counts, monocyte counts) or virologic (viral load [VL], biological characteristics of viral isolates) marker might be predictive of PE and whether any particular marker may be involved in the timing of clinical onset of PE. METHODS: A total of 189 children who were vertically infected with HIV-1 were studied retrospectively, 58 of whom fulfilled criteria of the American Academy of Neurology for PE. T-lymphocyte subsets and monocytes in peripheral blood were quantified by flow cytometry. HIV-1 RNA was measured in plasma using a quantitative reverse transcriptase polymerase chain reaction assay. Demographic, clinical, and viro-immunologic characteristics in infants were compared with control groups using logistic regression. Proportions were compared using the chi(2) test or Fisher exact test. For each child, immunologic and virologic markers were analyzed in parallel closely before clinical onset of PE and closely after PE onset and compared by using the Student t test for paired samples. RESULTS: Overall, mortality of 58 HIV-1-infected children who developed PE was significantly higher than of children who did not develop this complication. Blood CD8(+) T-lymphocytes <25% in the first months of life suggested a relative risk of progressing to PE 4-fold higher than those with CD8(+) >25% (95% confidence interval: 1.2-13.9) and remained statistically significant after adjustment for treatment. When we compared the PE-positive group with the acquired immunodeficiency syndrome (AIDS)/PE-negative group (children who developed clinical category C and without neurologic manifestations) in a cross-sectional study within 12 months before PE or AIDS diagnosis, respectively, the %CD8(+) T-lymphocytes were significantly lower in the PE-positive group. Normalized absolute counts of CD8(+) T-lymphocytes with respect to seroreverting children were significantly lower in the group of children with encephalopathy with respect to the AIDS/PE-negative group (data not shown). It is interesting that a statistically significant increase was observed in circulating monocyte percentages and absolute counts shortly before the first neurologic symptoms compared with values after PE was established and with those from HIV-1-infected controls. With respect to AIDS-related events, PE was strongly associated with anemia and lymphoid interstitial pneumonitis in the PE-positive group with respect to a group of children with AIDS but without PE. CONCLUSION: HIV-1 infection of the central nervous system (CNS) remains an important clinical concern. The first step toward PE prevention in HIV-1-infected children should be directed at predicting risk of PE and thus the prompt and reliable identification of infants who are at risk for CNS disease progression. Low blood CD8(+) T-lymphocytes is a strong early predictive marker of PE emergence in vertical HIV-1 infection. Indeed, among all of the immunologic and virologic variables assessed in this observational study, the only significant difference during the first months of life are the CD8(+) T-lymphocytes. A peak of significantly higher peripheral monocytes before the onset of PE with respect to established PE has not been previously described, and strengthens the growing evidence that an increased traffic of monocytes to the brain may be a key factor in triggering neurologic symptoms. The suppression of HIV-1 replication is dependent on the presence of a relatively small number of HIV-1-specifof HIV-1-specific CD8(+) T-lymphocytes, and it is possible that the duration of the neurologically asymptomatic phase for any given child may depend mostly on the magnitude of specific CD8(+) T-lymphocyte responses. Thus, a decrease of CD8(+) T-lymphocytes would diminish the host capacity to control viral infection, as reported in animal models, enabling infected macrophages to cross the blood-brain barrier. Our results advocate the use of CD8(+) T-lymphocyte and monocyte counts to follow-up HIV-1-infected children. We suggest that CD8(+) T-lymphocytes may be the nexus for many different aspects of the disease, namely loss of control of HIV-1 replication determining higher VL, increased traffic of activated and/or infected monocytes, spread of infection to immune sanctuaries, and finally clinical neurologic emergence of PE. Moreover, we suggest that CD8(+) T-lymphocytes or/and monocytes may be used as putative biological markers of neuropathogenicity. This might suggest their use in decision making of when to start more effective antiretroviral regimens for HIV-1 infection of the CNS and the need of new therapies either to preserve or to augment an adequate CD8(+) T-lymphocyte immune response. Early detection of children who are at risk for developing PE is particularly important because aggressive highly active antiretroviral therapy improves neurologic symptoms, allows possible use of neuroprotective treatment to prevent further development of encephalopathy, and emphasizes the relevance of developing therapies aimed to enhance CD8(+) T-lymphocyte function. In conclusion, the surrogate markers routinely used in clinical practice for HIV-1 infection (ie, CD4(+) T-lymphocyte counts and VL) seem to be insufficient to evaluate the clinical involvement of the CNS. Other systemic markers, as the recent proposed markers for PE evolution (cerebrospinal fluid VL by lumbar puncture and brain atrophy by cerebral magnetic resonance imaging) are undoubtedly more invasive than measuring CD8(+) T-lymphocyte and monocyte counts, when the neurologic manifestations of PE are still preventable.

CD8+ T-cell numbers predict the response to antiviral therapy in HIV-1-infected children.

Our objective was to study the probability of achieving undetectable viral load levels in HIV-1-infected children after 36 mo of highly active antiretroviral therapy (HAART). A prospective, multicenter, longitudinal study in 41 HIV-1-infected children on HAART was undertaken. Viral load was quantified using standard molecular assay. CD4+ and CD8+ T cell subsets were determined by flow cytometry. The probability of achieving undetectable viral load was determined using Kaplan-Meier curves according to groups by percentage CD8+ at baseline (CD8+ <25% or >25%). Lower baseline CD8+ T cell levels conditioned a less effective virological response to HAART in children, independent of baseline CD4+ T cell numbers and viral load levels. A greater number of children (81%) from CD8+ >25% group than from the CD8+ <25% (40%) presented undetectable viral load levels (p = 0.013). Additionally, the CD8+ >25% group showed a 4.5-fold higher (95% confidence interval: 1.1-19.2) relative proportion for achieving viral load <400 copies/mL than the CD8+ <25% group (p = 0.039). We concluded that monitoring CD8+ T cell numbers may be valuable in deciding when to start HAART in vertically HIV-1-infected children.

[Responses to antiretroviral treatments in vertically HIV-1-infected children]. / Respuesta al tratamiento antirretroviral en niños infectados verticalmente por el virus de la inmunodeficiencia humana tipo 1.

BACKGROUND AND OBJECTIVE: Our goal was to determine the probability of achieving a fall-off of viral load (VL) and an increase of CD4+T-lymphocytes by 36 months from the initiation of antiretroviral therapy (ART) in a cohort of HIV-infected children according to their baseline data. PATIENTS AND METHOD: This was retrospective multicenter observational study of virologic and immunologic markers in 128 HIV-1-vertically infected children on ART: 55 HIV-infected children on combination therapy (CT), and 73 HIV-infected children on highly active antiretroviral therapy (HAART). Viral load (VL) was quantified using a standard molecular assay. CD4+ and CD8+ T-cells subsets were determined by flow cytometry. RESULTS: The median time for a 10% rise of CD4+ T-lymphocytes was 35.7 months (95% confidence interval [95% CI], 15.5-55.9) after starting CT, and 11 months (95% CI, 7,7-14.3) after starting HAART. The median time for a VL fall to < 400 copies/ml was 29.6 months (95% CI, 9.4-49.7) after starting CT, and the median time for a VL fall to < 400 copies/ml was 10.9 months (95% CI, 0-21.9) after starting HAART. A 10% increase of CD4+ T-cells over baseline was associated with HAART, low CD4+ T-cells and high VL. On the other hand, a VL fall lower than 400 copies/ml was associated with HAART and low baseline VL. CONCLUSIONS: Our data indicate that HAART was better than CT in the control of VL and CD4+ T-cell increase. Also, baseline CD4+ T-cell and VL values helped to determine the response to ART in HIV-1 infected children.

Respuesta al tratamiento antirretroviral en niños infectados verticalmente por el virus de la inmunodeficiencia humana tipo 1 / Responses to antiretroviral treatments in vertically HIV-1-infected children

FUNDAMENTO Y OBJETIVO: Determinar la probabilidad de lograr una disminución de la carga viral (CV) y un incremento de células T CD4+ tras iniciar el tratamiento antirretroviral en una cohorte de niños infectados por el VIH-1 durante un período de 36 meses de seguimiento.PACIENTES Y MÉTODO: Estudio retrospectivo observacional multicéntrico de una cohorte de 128 niños infectados por el VIH-1: 55 niños VIH-1 en tratamiento combinado (TC) y 73 niños VIH-1 en tratamiento antirretroviral de gran actividad (TARGA). La CV se cuantificó en plasma por un método molecular estandarizado. Las subpoblaciones linfocitarias se determinaron por citometría de flujo.RESULTADOS: La mediana de tiempo para conseguir un incremento del 10 per cent de células T CD4+ fue de 35,7 meses (intervalo de confianza [IC] del 95 per cent, 15,5-55,9) después de empezar el TC, y 11 meses (IC del 95 per cent, 7,7-14,3) después de empezar el TARGA (p = 0,002). La mediana de tiempo en alcanzar una CV inferior a 400 copias/ml fue de 29,6 meses (IC del 95 per cent, 9,4-49,7) después de empezar el TC y 10,9 meses (IC del 95 per cent, 0-21,9) después de empezar el TARGA (p = 0,002). El incremento del 10 per cent de células T CD4+ estaba asociado al TARGA, bajo porcentaje de células T CD4+ y valores elevados de CV; mientras que los factores asociados con CV indetectable (CV < 400 copias/ml) fueron estar tratado con TARGA y CV basal baja.CONCLUSIONES: Nuestros datos indican que el TARGA es más eficaz que el TC en el control de la CV y el incremento de porcentaje de linfocitos T CD4+. Además, los valores basales del porcentaje de linfocitos T CD4+ y la CV ayudan a determinar la respuesta al tratamiento antirretroviral con más precisión en niños infectados por el VIH-1 (AU)

[Immunologic recovery after 2-years on HAART in vertically HIV-infected children]. / Reconstitución inmunológica en niños infectados por el virus de la inmunodeficiencia humana tipo 1 tras 2 años de tratamiento antirretroviral de gran actividad.

BACKGROUND: Our purpose was to carry out an analysis of T cells subsets involved in the recovery of the immune system in vertically HIV-1-infected children, on highly active antiretroviral therapy (HAART) over more than 24 months. PATIENTS AND METHOD: Seventeen HIV-1-infected children were studied: a) Res-group (HIV-1-infected children who were HAART-responders): 10 children in category C3 at entry in the study who, after more than 24 months on HAART, recovered CD4+ T cells (> 25% and 500 CD4+ T-cells/ml) and may control viral replicación, and b) non-Res group (HIV-1-infected children who did not respond to HAART): 7 children in category C3 at entry in the study who, after more than 24 months on HAART, did not recover CD4+ T-cells (< 15% or 200 CD4+ T-cells/ml) and did not control viral replication. As control group, 12 HIV-1-uninfected children with similar ages were included in the study. RESULTS: Children in the Res-group recovered the values of CD4+, CD8+ naïve (CD45RA+CD62L+) and memory (CD45RO+) T-cells until reaching the values of the control group. The differences were significant with regard to the non-Res group, except for the CD8+CD45RO+ T-cells of the Res and non-Res groups which were higher than the control group. Moreover, Res-group had values of CD8+HLA-DR+CD38+ T-cells lower than the non-Res group, yet both HIV-1 groups (Res and non-Res) had significantly higher values of CD4+ and CD8+ activated (HLA-DR+CD38+) T-cells than the control group. CONCLUSIONS: The recovery of the immune system induced by HAART in HIV-1-infected children seems to be the consequence of the decrease of the immune system chronic activation and the recovery of naïve T-cells.

Reconstitución inmunológica en niños infectados por el virus de la inmunodeficiencia humana tipo 1 tras 2 años de tratamiento antirretroviral de gran actividad / Immunologic recovery after 2-years on HAART in vertically HIV-infected children

FUNDAMENTO: Realizar un análisis de las subpoblaciones T implicadas en la recuperación del sistema inmunitario en niños infectados por el VIH-1 con terapia antirretroviral de gran actividad (TARGA) durante más de 24 meses. PACIENTES Y MÉTODO: Se estudió a 17 niños infectados por el VIH-1: a) grupo Res (niños infectados por el VIH-1 respondedores a TARGA): 10 niños en categoría C3 al entrar en el estudio y tras más de 24 meses con TARGA recuperan células T CD4+ (> 25 por ciento y 500 células T CD4+/ml) y controlan la replicación viral, y b) grupo no-Res (niños infectados por el VIH-1 no respondedores a TARGA): 7 niños en categoría C3 al entrar en el estudio y que tras más de 24 meses con TARGA no recuperan células T CD4+ (< 15 por ciento o 200 células T CD4+/ml) y no controlan la replicación viral. Como grupo control no infectados por el VIH-1 se incluyó a 12 niños no infectados por el VIH de edades similares. RESULTADOS: El grupo Res recuperó los valores de células T CD4+ y CD8+ virgen (CD45RA+CD62L+) y memoria (CD45RO+) hasta alcanzar los valores del grupo control, siendo las diferencias significativas con respecto al grupo no-Res, excepto para las células CD8+CD45RO+ de los grupos Res y no-Res, que fueron más elevadas que el grupo control. Además, el grupo Res tuvo valores más bajos de células CD8+HLA-DR+CD38+ que el grupo no-Res, aunque ambos grupos VIH-1 (Res y no-Res) tuvieron valores significativamente más altos de células T CD4+ y CD8+ activadas (HLA-DR+CD38+) que el grupo control. CONCLUSIONES: la recuperación del sistema inmunitario inducida por la TARGA en los niños infectados por el VIH-1 parece ser la consecuencia de la disminución de la activación crónica del sistema inmunitario y de la recuperación de las células T virgen. (AU)

[Different immune profiles according to the immunological and clinical progression in vertically HIV-infected children]. / Variación del perfil inmunológico en función de la progresión de la infección por el virus de la inmunodeficiencia humana en niños tratados con terapia antirretroviral.

BACKGROUND: Our goal was to evaluate immunologic profile differences of HIV-infected children on antiretroviral treatment (ART). PATIENTS AND METHODDS: We studied 23 HIV-vertically infected children: a) N-A1 group: 10 HIV-infected children in A1 category; b) N-B2 group: 6 HIV-infected children in B2 category, and c) N-C3 group: 7 HIV-infected children in C3 category. We also studied 13 healthy age-matched HIV-negative children as controls. Cell proliferation was evaluated by incorporation of [3H]-Thymidine. The cytokine production in culture was quantified using commercially available specific ELISA assays. T-cell subsets were determined by flow cytometry. RESULTS: Stimulation indexes of PHA, PWM, and anti-CD3+ anti-CD28 in N-A1 group were higher than in N-C3 group. In unstimulated PBMC, TNF-alpha production of HIV-infected children was higher than the control group (p < 0.05). However, in stimulated PBMC, TNF-alpha production in N-B2 and N-C3 groups was lower than the control group (p < 0.05). In HIV-infected children, CD8+ CD45RA+ CD62L+ T-cells were significantly lower (p < 0.01) and CD8+ CD45RO+ T-cells were higher (p < 0.05) than the control group. Moreover, in NA-1 group, CD4+ CD45RA+ CD62L+ T-cells were higher, and CD4+ CD45RO+ and CD8+ CD45RO+ T-cells were lower, than in N-B2 and N-C3 groups (p < 0.05). On the other hand, CD45RO+, CD45RO+ CD38+, HLA-DR+, CD38+ HLA-DR+ and CD38+ CD4+ and CD8+ T-cells were higher in N-C3 group than the N-A1 and control groups, except for CD4+ CD38+ T-cells. Activated CD8+ T-cells in N-A1 group were higher than in control group (p < 0.01). CONCLUSION: Our data demonstrate that in spite of ART, there still remain important differences in the immunologic status of HIV-infected children depending on the HIV-infection stage.

Variación del perfil inmunológico en función de la progresión de la infección por el virus de la inmunodeficiencia humana en niños tratados con terapia antirretroviral / Different immune profiles according to the immunological and clinical progression in vertically HIV-infected children

FUNDAMENTO: Evaluar los cambios producidos en el sistema inmunitario de niños infectados por el virus de la inmunodeficiencia humana (VIH) tratados con terapia antirretroviral. PACIENTES Y MÉTODO: Se estudió a 23 niños infectados verticalmente por el VIH: a) N-A1: 10 niños en categoría A1; b) N-B2: 6 niños en categoría B2, y c) N-C3: 7 niños en categoría C3, y 13 niños sanos sin VIH como grupo control. La respuesta proliferativa y la producción de citocinas de las CMSP frente a mitógenos fue evaluada por incorporación de [3H]-timidina y enzimoinmunoanálisis, respectivamente. Las subpoblaciones linfocitarias T CD4+ y T CD8+ se cuantificaron por citometría de flujo. RESULTADOS: Los niños N-A1 tuvieron índices de estimulación frente a PHA, PWM y anti-CD3+ anti-CD28 similares al grupo control y mayores que los niños N-C3. La producción de TNF- por las CMSP sin estimular de los niños VIH fue más elevada que en el grupo control (p < 0,05), pero tras estimulación con PHA, los niños N-B2 y N-C3 tuvieron valores más bajos que el grupo control. Los niños infectados por el VIH tuvieron valores inferiores al grupo control de CD8+ CD45RA+ CD62L+ (p < 0,01) y superiores de CD8+ CD45RO+ (p < 0,05). Además, los niños NA-1 tuvieron valores mayores de CD4+ CD45RA+ CD62L+ y menores de CD4+ CD45RO+ y CD8+ CD45RO+ que los niños N-B2 y N-C3 (p < 0,05). Por otro lado, los niños N-C3 tuvieron valores mayores de células T CD4+ y T CD8+ que expresan CD45RO+, CD45RO+ CD38+, HLADR+, CD38+ HLA-DR+ y CD38+ que los grupos N-A1 y control, excepto para CD4+ CD38+. El grupo N-A1 también tuvo valores de células T CD8+ activadas más altos que el control (p < 0,01). CONCLUSIÓN: Nuestros datos demuestran que, a pesar del tratamiento antirretroviral, siguen existiendo importantes diferencias en el perfil inmunológico de los niños con infección por el VIH en los distintos estadios clínicos de la enfermedad (AU)

Relación de las subpoblaciones de linfocitos T con los marcadores pronósticos de la infección pediátrica por el Virus de la Inmunodeficiencia Humana / Relationship between T-cells subsets and prognostic markers in HIV-1-infected children

FUNDAMENTO: Investigar la relación entre las subpoblaciones de linfocitos T de sangre periférica con el marcador inmunológico (porcentaje de células T CD4+) y virológico (carga viral [CV]) en niños con infección por el VIH-1. PACIENTES Y MÉTODO: Hemos estudiado a 50 niños infectados verticalmente por el VIH-1 que recibían tratamiento antirretroviral estable (AR). Las subpoblaciones de linfocitos T se cuantificaron mediante citometría de flujo. La CV se cuantificó usando métodos moleculares estandarizados. RESULTADOS: Las células T CD4+ y CD8+ de memoria (CD45RO+), memoria activada (CD45RO+ HLA-DR+) y memoria que expresan L-selectina (CD45RA-CD62L+) se correlacionaron positivamente con la CV y negativamente con el porcentaje de células T CD4+. Las células vírgenes (CD45RA+CD62L+) tuvieron correlación positiva con el porcentaje de células T CD4+ y negativa con la CV. Las células T CD4+ y CD8+ que expresan HLA-DR+, CD38+ o HLA-DR+CD38+ se correlacionaron positivamente con la CV y negativamente con el porcentaje de células T CD4+, excepto CD4+CD38+, que no se asoció con la CV, y se correlacionó positivamente con el porcentaje de células T CD4+. Las células CD8+ CD28+ se correlacionaron positivamente con porcentaje de células T CD4+ y negativamente con la CV, mientras que CD8+CD57+ y CD8+CD28-CD57+ tuvieron una asociación opuesta a CD8+CD28+. CONCLUSIONES: Nuestros datos indican que existe una asociación de las distintas subpoblaciones linfocitarias de memoria, vírgenes, activadas y efectoras con los dos marcadores más habitualmente usados en la clínica (CV y porcentaje de células T CD4+). Algunas de estas subpoblaciones pueden ser de ayuda para determinar el estado inmunológico y virológico de los niños infectados por el VIH-1 (AU)

Marcadores predictivos de progresión a sida en niños infectados por transmisión vertical por el virus de la inmunodeficiencia humana tipo 1 / Prognostic markers of progression to aids in infants vertically infected by human immunodeficiency virus type-1

Fundamento: Estudiar el valor predictivo, individual y en conjunto, del porcentaje de linfocitos T CD4+, CD8+ y la carga viral plasmática (copias/ml), de progresión a sida en niños infectados verticalmente por el VIH-1. Pacientes y método: El estudio incluye una cohorte de 115 niños infectados por el VIH 1 mayores de 12 meses de edad. La carga viral se cuantificó en el plasma por un método molecular estandarizado. Las subpoblaciones linfocitarias se determinaron por citometría de flujo. Resultados: Los niños con una mediana de carga viral mayor de 4,5 log10 (p < 0,001) y porcentaje de CD8+ inferior a 25 por ciento (p = 0,05) durante el seguimiento tuvieron una media de tiempo de progresión a sida más baja. El riesgo relativo (RR) de progresión a sida fue mayor de 7 veces en los niños con una carga viral de más de 4,5 log10 de la mediana. En el caso de la carga viral como variable continua, encontramos que el riesgo de progresión a sida es superior a 3,5 por cada aumento de log10 de carga viral. El porcentaje de CD8+ tuvo un RR de progresión a sida de 0,95/ por ciento CD8+ a la entrada en el estudio y de 0,19/ por ciento CD8+ durante el seguimiento, indicando protección frente a la progresión a sida. Conclusiones: Los valores individuales durante el seguimiento, pero no los basales, del porcentaje de linfocitos T CD8+ y carga viral ayudan a determinar el riesgo de progresión a sida en niños infectados por el VIH-1, y el uso de los dos marcadores juntos predice con más precisión el pronóstico de la enfermedad. (AU)