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Aims: To assess the 'real life' effectiveness of different antiretroviral therapies (ART). Methods: A retrospective multicentre observational study in 150 HIV-1 vertically infected children on the progression to AIDS (study [...]

Unlabelled: Treatment with highly active antiretroviral therapy (HAART) has been shown to modify viral replication dynamics and lead to a significant recovery of CD4+ T-cells. A retrospective multicentre observational study was performed in a non-study population of 151 HIV-1-infected children, categorized into four groups according to therapy: untreated (NT), on monotherapy (MT) with a nucleoside inhibitor, on combination therapy (CT) with two nucleoside inhibitors, and on HAART, protease inhibitor containing regimens, to assess the "real-life" effectiveness of these different therapies on plasma viral load (VL) and CD4+ T-cells. VL was quantified using a standard molecular assay. CD4+ and CD8+ T-cells subsets were determined by flow cytometry. The HAART group showed the highest relative proportion (RP) of increases in 5, 10, 15 and 20% of CD4+ T-cells over baseline, and the earliest fall-off of VL (0.5, 1, 1.5 and 2 log10 copies ml-1). The RP of the fall-off of 0.5, 1, 1.5 and 2 log10 VL below baseline was 3-fold higher in HAART group than in the MT and CT groups. However, no differences were found among the groups of treated children in reaching undetectable VL.Conclusion: A better evolution of VL and CD4+ T-cells was evident in children on HAART, indicating a positive effect on the immune system and clinical status, inhibiting HIV-1 replication and enabling the recovery of CD4+ T-cell counts. [ABSTRACT FROM AUTHOR]

Unlabelled: This study measured cytokine production by mitogen-stimulated peripheral blood mononuclear cells (PBMCs) from 55 human immunodeficiency virus (HIV)-infected children born to HIV-infected mothers, and compared it with vertically exposed but uninfected age-matched children. A significant defect was observed in Th1 cytokine production [interferon-gamma and interleukin-2 (IL-2)] in HIV-infected children compared with controls, but without a concomitant increase in Th2 cytokines. Indeed, IL-5 and IL-10 production was even lower in HIV-infected children than in controls, with the decrease in IL-5 being the best predictive marker of immunodeficiency. In addition, an increased release of tumour necrosis factor-alpha (TNF-alpha) that correlated well with CD4+ levels, and a positive correlation of the TNF-alpha/IL-10 ratio with disease progression was observed. A correlation between AIDS-free status and higher %CD4+ and %CD8+ T-lymphocytes and RANTES (regulated on activation, normal T-cell expressed and secreted) production was also found.Conclusion: A dysfunctional cytokine production of PBMCs was observed in HIV-infected children in both Th1 and Th2 cytokines due to quantitative and qualitative defects induced by HIV-1. An important observation was an increased RANTES production associated with viral isolates of NSI/R5 phenotype and S/L kinetics. [ABSTRACT FROM AUTHOR]

The objective of this study was to investigate the relationship between peripheral blood CD4[sup +] T cell subsets and routine viro-immunological markers in vertically HIV-1-infected children undergoing highly active antiretroviral therapy (HAART). CD4[sup +] and CD8[sup +] T cell subsets were examined by three-colour flow cytometry. Plasma viraemia was quantified by a standardized molecular assay. A negative correlation between the %CD4[sup +] T cells and both viral load and the %CD8[sup +] T cells was observed. A strong positive correlation between the %CD4 T cells and naïve, CD38[sup +] and non-activated CD4[sup +] T cell subsets was found, whereas the %CD4 T cells correlated negatively with the numbers of memory, activated and memory-activated CD4[sup +] T cell subsets. Elevated percentages of CD8 T cells were associated with increased memory and CD4[sup +] CD62L-T cell subsets, whereas the naïve and CD4[sup +] HLA-DR[sup ]CD38[sup +] subsets negatively correlated with the CD8%. Co-expression of CD62L on memory CD4[sup +] cells and high expression of HLA-DR (but not of CD38) were associated with high viral load. No association between viral load and naïve CD4[sup +] T cells was observed. Specific CD4[sup +] T cell subsets may be more informative than routine surrogate markers in defining the evolution of HIV infection and immune reconstitution in children. [ABSTRACT FROM AUTHOR]

Background: In the past few decades, researchers have made promising progress, including the development of immune checkpoint inhibitors (ICIs) in the therapy of bladder cancer (BLCA). Existing studies mainly focus on single immune checkpoint inhibitors but lack relevant studies on the gene expression profiles of multiple immune checkpoints. Methods: RNA-sequencing profiling data and clinical information of BLCA patients and normal human bladder samples were acquired from the Cancer Genome Atlas and Gene Expression Omnibus databases and analyzed to identify different expression profiles of immune checkpoint genes (ICGs) after consensus clustering analysis. Based on the 526 intersecting differentially expressed genes, the LASSO Cox regression analysis was utilized to construct the ICG signature. Results: According to the expression of ICGs, BLCA patients were divided into three subtypes with different phenotypic and mechanistic characteristics. Furthermore, the developed ICG signature were independent predictors of outcome in BLCA patients, and was correlated with the immune infiltration, the expression of ICGs and chemotherapeutic effect. Conclusions: This study systematically and comprehensively analyzed the expression profile of immune checkpoint genes, and established the ICG signature to investigate the differences in ICGs expression and tumor immune microenvironment, which will help risk stratification and accelerate precision medicine. Finally, we identified KRT23 as the most critical model gene, and highlighted KRT23 as a potential target to enhance immunotherapy against BLCA. [ABSTRACT FROM AUTHOR]

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., (Copyright © 2014 Mosby, Inc. All rights reserved.)

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.

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.

T cells recognize antigens via their cell surface TCR and are classified as either αβ or γδ depending on the variable chains in their TCR, α and β or γ and δ, respectively. Both αβ 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 αβ T cell-specific defect. Here, we report 2 unrelated cases of SCID with a selective block in αβ 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 αβ 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 αβ T cells, surface TCR expression was more reduced in γδ than in αβ T cells. Analysis of individuals with this CD3D mutation thus demonstrates the contrasting CD3δ requirements for αβ 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.

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., (Copyright 2009 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.)

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.

Neurodevelopmental proteasomopathies constitute a recently defined class of rare Mendelian disorders, arising from genomic alterations in proteasome-related genes. These alterations result in the dysfunction of proteasomes, which are multi-subunit protein complexes essential for maintaining cellular protein homeostasis. The clinical phenotype of these diseases manifests as a syndromic association involving impaired neural development and multisystem abnormalities, notably craniofacial anomalies and malformations of the cardiac outflow tract (OFT). These observations suggest that proteasome loss-offunction variants primarily affect specific embryonic cell types which serve as origins for both craniofacial structures and the conotruncal portion of the heart. In this hypothesis article, we propose that neural crest cells (NCCs), a highly multipotent cell population, which generates craniofacial skeleton, mesenchyme as well as the OFT of the heart, in addition to many other derivatives, would exhibit a distinctive vulnerability to protein homeostasis perturbations. Herein, we introduce the diverse cellular compensatory pathways activated in response to protein homeostasis disruption and explore their potential implications for NCC physiology. Altogether, the paper advocates for investigating proteasome biology within NCCs and their early cranial and cardiac derivatives, offering a rationale for future exploration and laying the initial groundwork for therapeutic considerations. [ABSTRACT FROM AUTHOR]

Globally, around 11% of neonates are born prematurely, comprising a highly vulnerable population with a myriad of health problems. Premature births are often accompanied by an underdeveloped immune system biased towards a Th2 phenotype and microbiota dysbiosis. Typically, a healthy gut microbiota interacts with the host, driving the proper maturation of the host immunity. However, factors like cesarean section, formula milk feeding, hospitalization in neonatal intensive care units (NICU), and routine antibiotic treatments compromise microbial colonization and increase the risk of developing related diseases. This, along with alterations in the innate immune system, could predispose the neonates to the development of respiratory diseases later in life. Currently, therapeutic strategies are mainly focused on restoring gut microbiota composition using probiotics and prebiotics. Understanding the interactions between the gut microbiota and the immature immune system in premature neonates could help to develop novel therapeutic strategies for treating or preventing gut–lung axis disorders. [ABSTRACT FROM AUTHOR]

Limited molecular data exist on the prevalence and subtype distribution of Blastocystis spp., the most prevalent parasite in human and animal feces worldwide. A total of 44 different subtypes (STs) of Blastocystis are currently recognized based on the sequence of the small subunit ribosomal RNA (SSU-rRNA) gene. This is a molecular study of Blastocystis spp. in hospitalized patients with gastrointestinal symptoms in northern Spain. We analyzed 173 Blastocystis-positive patients with gastrointestinal symptoms by using nested PCR for molecular detection, subtype identification, phylogenetic analyses, and genetic diversity assessment. ST2 (34.1%) and ST3 (34.7%) predominated, followed by ST1 (15.6%) and ST4 (15.6%). Mixed infections with different subtypes were observed in some patients. Sequence analysis revealed for the first time in European humans the allele 88 (a variant of ST1). In other cases, alleles commonly found in animal samples were detected (allele 9 in ST2, allele 34 in ST3, and allele 42 in ST4). Phylogenetic analysis showed high variability in ST1 and ST2, suggesting a polyphyletic origin, while both ST3 and ST4 exhibited higher genetic homogeneity, indicating a possible monophyletic origin and recent transmission to humans. These data confirm Blastocystis spp. subtype diversity and may help in understanding the evolutionary processes and potential zoonotic transmission of this parasite. [ABSTRACT FROM AUTHOR]

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.

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.

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.

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.

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.

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.

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.

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.

Background: To investigate the relationship between peripheral blood T-cell subsets and both CD4+ T-cell percentage and viral load (VL) in HIV-1-infected children., Patients and Method: We studied 50 HIV-1-infected children on antiretroviral therapy. T-cell subsets were determined by flow cytometry. The VL was quantified using standardized molecular methods., Results: Memory (CD45RO+), activated memory (CD45RO+HLA-DR+) and CD45RA-CD62L+ (memory cells expressing L-selectin) CD4+ and CD8+ T-cells correlated positively with the VL and negatively with the percentage of CD4+ T-cells. Inversely, naive CD4+ and CD8+ T-cells (CD45RA+CD62L+) correlated positively with the percentage of CD4+ T-cells and negatively with the VL. HLA-DR+, CD38+ or HLA-DR+CD38+CD4+ and CD8+ T-cells correlated also positively with the VL and negatively with the percentage of CD4+ T-cells (with the exception of CD4+CD38+ which did not show any association with the VL). CD8+CD28+ T-cells correlated positively with the percentage of CD4+ T-cells and negatively with the VL, whereas CD8+ CD57+ and CD8+CD28-CD57+ exhibited an opposite association., Conclusions: Our data suggest a relationship between the different lymphocyte subsets (memory, naïve, activated and effector T-cells) and the most commonly used markers in clinical practice, namely the viral load and the CD4+ T-cell percentage. Some of these subsets may be useful to determine the virologic and immunologic status in HIV-1-infected children.

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.

Background: To study the prognostic AIDS progression value of the percentage of CD4+, CD8+, and plasma viral load (VL) (copies/ml) in HIV-1-vertically infected children., Patients and Method: We study a cohort of 115 HIV-1 infected children older than 12 months of age. The VL was quantified using standard molecular assay. CD4 and CD8 T lymphocytes were determined by flow cytometry., Results: The children with a median of VL > 4.5 log10 (p < 0.001) and percentage of CD8+ < 25% (p = 0.05) during follow-up, progressed faster to AIDS than children with a median of VL < 4.5 log10 and CD8 > 25%. The relative risk (RR) of AIDS progression was 7-fold higher in children with median VL above 4.5 log10. When considering VL as a continuous variable, risk of progression to AIDS is 3.5-fold higher for each increase of one log10 of VL. The percentage of CD8+ T-cells had a RR of AIDS progression of 0.95/% CD8+ at entry to the study and of 0. 19/% CD8+ during follow-up, indicating protection against progression to AIDS., Conclusions: Our results indicate that each basal values at entry in the study and during the follow-up of the percentage of CD8+ and VL helps to determine the risk of AIDS progression in HIV-1-infected children. More interestingly, the use of the two predictive markers together had higher predictive value.

Aim: To assess the relationship among plasma TNF-a and cICAM-1 levels and plasma viral load (VL) in HIV-infected children and to compare these values with those of healthy non-HIV infected children., Patients and Methods: We studied 44 HIV-infected children and 38 non-HIV-infected children. The VL was quantified using standard molecular assay. CD4 and CD8 lymphocyte subpopulations were determined by flow cytometry. TNF-a and cICAM-1 were quantified using commercially available specific enzyme-linked immunosorbent assay (ELISA)., Results: Levels of TNF-a and cICAM-1 were higher in HIV-infected children than in non-HIV infected children. HIV-infected children with VL > 50000 copies/ml had higher levels of TNF-a (12.83; 95% CI: 24.71 to 0.95 pg/ml) and cICAM-1 (248.94; 95% CI: 419.01 to 78.84 ng/ml) than HIV-infected children with VL < 50000 copies/ml. Interestingly, we found an increase of 6.57 pg/ml of TNF-a and 119.97 ng/ml of cICAM-1 levels for each log10 of VL., Conclusions: HIV-infected children had higher levels of TNF-a and cICAM-1 than healthy controls. Our data indicate a positive correlation among plasma TNF-a and cICAM-1 and VL levels.

We have investigated the relationship between disease progression and several immunologic and virologic markers of HIV infection. Plasma samples from infants born to HIV-1-infected mothers were collected at birth and at 1, 2, 4, 6, 9, 12, 15, and 18 mo of age and subsequently were assayed every 6 mo for viral load, viral phenotype, and lymphocyte populations. A cutoff level of 25% indicative of a preserved immunologic status, both of CD4+ and CD8+ blood T cells, was associated with significant differences in disease progression (p = 0.04 and 0.02, respectively). Infants with median CD4+ T cells <25% had a relative risk of progression to AIDS 3.35-fold higher than those with CD4+ above this level (p = 0.05). The relative risk of progression to AIDS for infants with median CD8+ <25% was 4.95-fold higher than for those with CD8+ percent above this threshold (p = 0.03). Similarly, a cutoff level of viral load of 5.5 log10 copies/mL was indicative of a worse prognosis. Infants with median viral load >5.5 log10 copies/mL had a relative risk of progression to AIDS 23.72-fold higher (p = 0.0001) than those with median viral load below this threshold. Interestingly, changes from a slow replication and low titer to a rapid replication and high titer of virus and from nonsyncytium-inducing to syncytium-inducing viral phenotype were indicative of progression to AIDS. Our results indicate that biologic phenotype of viral isolates and CD8+ T-lymphocyte percentages in peripheral blood as well as viral load and CD4+ T-lymphocyte percentages could predict rapid progression to advanced HIV-1 disease in HIV-1-infected infants.

Objective: To study the relationship among clinical symptoms and biological markers as predictive value of progression to death in HIV-1 vertically infected infants., Patient and Methods: We carry out a prospective study in 43 HIV-1 infants with a mean age of 4.27 (range: 0-11.8 months). None of the infants' mothers had received any antiviral treatment during pregnancy. None of the infants were breastfed. They were routinely assessed for clinical symptoms during follow-up., Results: Cox regression analysis was used to study the hazard ratio (HR) of progression to death. For the median viral load > 5 log10, the HR was 6.42 (95% CI, 1.28-32.03) (p = 0.023) and 6.84 (95% CI, 1.52-30,69) (p = 0.012) for biological phenotype of viral isolates with rapid replication and high titter (R/H-X4). We also study the predictive value of the clinical symptoms and we observe that the symptoms with more HR of progression to death were the progressive encephalopathy (3.60 [95% CI, 0.92-14.06; p = 0.065]) and the cardiopathy (6.29 [95% CI, 1.59-24.85; p = 0.008])., Conclusions: Our data indicate that viral load > 5 log10 and biological phenotype R/H-X4 of virus isolates along the study are predictive markers of progression to death. In addition, the progressive encephalopathy and cardiopathy were also markers of progression death.