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The CC-chemokine receptor (CCR)-5 is thought to be the main co-receptor used by macrophage-tropic HIV-1 strains for cell entry. The presence of a 32 base-pair deletion in both CCR-5 alleles (CCR-5 32/CCR-5 32) in exposed uninfected... more
The CC-chemokine receptor (CCR)-5 is thought to be the main co-receptor used by macrophage-tropic HIV-1 strains for cell entry. The presence of a 32 base-pair deletion in both CCR-5 alleles (CCR-5 32/CCR-5 32) in exposed uninfected individuals confers resistance against macrophage-tropic isolates usually involved in HIV-1 transmission although recent findings suggest that such homozygosity fails to confer total resistance against HIV-1 infection. 64 blood donors and 328 children born to HIV-1-infected mothers attending the Hospital de Pediatria "J.P. Garrahan" in Buenos Aires between July 1994 and March 1997 participated in a study conducted to determine the frequency and role of CCR-5 32 allele in the perinatal transmission of HIV-1 in Argentina. 138 of the children were infected with HIV-1 while 190 were uninfected. The presence of the 32 allele was determined through polymerase chain reaction amplification of CCR-5 sequences. 3 (4.7%) of the 64 blood donors were heterozygous CCR-5/CCR-5 32 while the remaining subjects were homozygous for the wild-type allele. The allele frequencies were 0.976 and 0.024 for the wild-type and mutant alleles respectively. 21 children were heterozygous and 1 was homozygous for CCR-5 32 for a CCR-5 32 allelic frequency of 0.035. No difference in CCR-5 genotype distribution was found between blood donors and children at risk. 8 of the HIV-1-infected and 13 of the uninfected children were heterozygous while 1 uninfected child was homozygous for the CCR-5 32 allele. The genotype distribution did not differ significantly between HIV-1-infected and uninfected populations and were in equilibrium according to the Hardy-Weinberg equation.
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Background Increasing evidence from adult cohorts suggests an important role of HIV-1 pretreatment drug resistance (PDR) in ART failure, in spite of treatment being fully active according to baseline genotyping tests. Whether this is also... more
Background Increasing evidence from adult cohorts suggests an important role of HIV-1 pretreatment drug resistance (PDR) in ART failure, in spite of treatment being fully active according to baseline genotyping tests. Whether this is also true for children is unknown. Methods Virological and immunological parameters were longitudinally assessed in a group of 39 HIV-1 vertically infected children starting first-line lopinavir/ritonavir-based ART at a median of 5.0 months (IQR = 3.0–9.0). Evolution of viral load (VL) over time was compared between children with and without baseline PDR, as defined by the WHO mutation list. Results Resistance-associated mutations (RAMs) in the HIV-1 pol gene were present in nine HIV-1-infected children (23%) before initiation of first-line ART (PDR group). Of them, six carried RAMs associated with NNRTIs (NNRTI-PDR subgroup). At 4–8 weeks after ART initiation, the proportion of children achieving ≥1 log VL reduction was 87% for the no-PDR group versus 33% and 16.7% for the PDR group and the NNRTI-PDR subgroup, respectively. During follow-up, children with no PDR reached virological suppression almost four times faster than children with PDR or NNRTI-PDR [no-PDR = 631 days and PDR = 2134 days (P = 0.1249) and NNRTI-PDR = 2134 days (P = 0.0447)]. CD4 T cells remained similar between the study groups over time. Conclusions HIV-1 baseline genotyping at diagnosis in vertically infected children is important for improved personalized medicine. While the mechanism is unclear, cases with PDR (particularly to NNRTIs) require closer monitoring of their first-line ART regimens in order to avoid early virological failures and prevent further accumulation of resistance.
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BackgroundIn prior studies, HIV-1 BF recombinants with subtype F integrases failed to develop resistance to raltegravir through the Q148H mutational pathway. We aimed to determine the role of subtype-specific polymorphisms in integrase on... more
BackgroundIn prior studies, HIV-1 BF recombinants with subtype F integrases failed to develop resistance to raltegravir through the Q148H mutational pathway. We aimed to determine the role of subtype-specific polymorphisms in integrase on drug susceptibility, viral replication and integration.MethodsIntegrase sequences were retrieved from the Los Alamos Database or obtained from the Garrahan HIV cohort. HIV-1 infectious molecular clones with or without Q148H (+ G140S) resistance mutations were constructed using integrases of subtype B (NL4-3) or F1(BF) ARMA159 and URTR23. Integrase chimeras were generated by reciprocal exchanges of a 200 bp fragment spanning amino acids 85–150 of the catalytic core domain (CCD) of NL4-3-Q148H and either ARMA159-Q148H or URTR23-Q148H. Viral infections were quantified by p24 ELISA and Alu-gag integration PCR assay.ResultsAt least 18 different polymorphisms distinguish subtype B from F1(BF) recombinant integrases. In phenotypic experiments, p24 at Day 15 post-infection was high (105–106 pg/mL) for WT and NL4-3-Q148H; by contrast, it was low (102–104 pg/mL) for both F1(BF)-Q148H + G140S viruses, and undetectable for the Q148H mutants. Compared with WT viruses, integrated DNA was reduced by 5-fold for NL4-3-Q148H (P = 0.05), 9-fold for URTR23-Q148H (P = 0.01) and 16000-fold for ARMA159-Q148H (P = 0.01). Reciprocal exchange between B and F1(BF) of an integrase CCD region failed to rescue the replicative defect of F1(BF) integrase mutants.ConclusionsThe functional impairment of Q148H in the context of subtype F integrases from BF recombinants explains the lack of selection of this pathway in vivo. Non-B polymorphisms external to the integrase CCD may influence the pathway to integrase strand transfer inhibitor resistance.
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The outcome of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in cancer pediatric patients was initially uncertain. The objective of this study was to describe the characteristics and outcome of cancer patients and... more
The outcome of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in cancer pediatric patients was initially uncertain. The objective of this study was to describe the characteristics and outcome of cancer patients and hematopoietic stem cell transplant recipients from 0 to 19 years with detectable SARS-CoV-2 from April 23, 2020, to April 30, 2022, treated in a tertiary-level hospital in Argentina. A total of 348 cases were registered in 339 patients. The median age was 89.5 (3 to 224) months. The sex was predominantly male: 193 (55.5%). The most common malignant disease was leukemia (42.8%). One hundred four cases (29.9%) had comorbidities. Of the 346 cases with an available blood count, 17.6% had a lymphocyte count <300/mm3. Fever was the most common symptom. In most cases (93.1%) presented asymptomatic or mild disease. Twenty-one cases (6%) presented severe or critical status. Eleven of 24 admissions to the intensive care unit were due to COVID-19 (coronavi...
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Real time PCR is one of the major tools for molecular diagnosis, however not always reaches the required sensitivity, especially in detecting early infectious disease. To overcome this problem, nested PCR is commonly performed, since it... more
Real time PCR is one of the major tools for molecular diagnosis, however not always reaches the required sensitivity, especially in detecting early infectious disease. To overcome this problem, nested PCR is commonly performed, since it is highly sensitive, but it is time-consuming, prone to cross-contamination and difficult to standardize. Therefore, we developed a sensitive and specific single-tube nested real-time PCR (STN-real-time PCR) assay and evaluated its clinical utility on early infant HIV-1 diagnosis (EID). The STN-real-time PCR enables the simultaneous amplification of four HIV-1 specific amplicons by the use of an internal and external pair of primers targeting ltr/gag region, and another one corresponding to human albumin as an internal control. Thermocycling had different annealing temperatures to favor the sequential use of each pair of primers, and included an initial touchdown step to broaden specificity and increase sensitivity. Finally, HIV-1 was detected by melting curve analysis. A total of 234 samples collected retrospectively and prospectively from HIV-1 exposed infants aged <18 months were used to evaluate the performance of the assay and compare it with a routine diagnostic nested-multiplex PCR. The developed assay had a limit of detection of 3 copies of HIV-1 DNA per reaction and had a sensitivity of 31% more than routine diagnostic nested-multiplex PCR when testing samples near delivery. In conclusion, we developed a new assay by turning a conventional nested-PCR into a faster, more sensitive and feasible STN-real-time PCR assay for EID and potentially useful for detection of pathogens with variable genomes and present in low copy numbers.
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Stenotrophomonas maltophilia intrinsic resistance to β-lactams is mediated by two chromosomal β-lactamases, L1 and L2, whose induction depends on AmpR. Its quorum sensing (QS) signal, the diffusible signal factor (DSF), has a positive... more
Stenotrophomonas maltophilia intrinsic resistance to β-lactams is mediated by two chromosomal β-lactamases, L1 and L2, whose induction depends on AmpR. Its quorum sensing (QS) signal, the diffusible signal factor (DSF), has a positive role in biofilm production, virulence and induction of β-lactamases. We hypothesized that AmpR has a role in virulence, biofilm production and QS system. Studies were done on S. maltophilia K279a, K279a ampRFS (ampR deficient mutant) and K279aM11 (constitutively active AmpR mutant). K279a ampRFS showed the highest biofilm biomass, thickness and 3D organization. Conversely, K279aM11 was the least efficient biofilm former strain. qRT-PCR showed that spgM, related to biofilm formation and virulence, was upregulated in K279a ampRFS and downregulated in K279aM11. A constitutively active AmpR led to a reduction of DSF production, while K279a ampRFS was the highest producer. Consequently, qRT-PCR showed that AmpR negatively regulated rpfF expression. K279a ampRFS presented the highest oxidative stress resistance, overexpressed sodA gene and showed the highest virulence in the Galleria mellonella killing assay. This is the first evidence of the function of AmpR as a dual regulator in S. maltophilia with a positive role in β-lactam resistance and a negative role in DSF production, biofilm formation, oxidative stress resistance and virulence.
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Research Interests: Philosophy and Humanities
Resumen. ISGENHIV es la primera herramienta bioinformatica para el analisis conjunto de datos clinicos y geneticos aplicada al ambito hospitalario. Fue construida por un equipo interdisciplinario de especialistas en biologia molecular y... more
Resumen. ISGENHIV es la primera herramienta bioinformatica para el analisis conjunto de datos clinicos y geneticos aplicada al ambito hospitalario. Fue construida por un equipo interdisciplinario de especialistas en biologia molecular y en informatica, que tomaron el desafio de unir distintos conocimientos y experiencias para mejorar la calidad del seguimiento de los ninos con HIV.
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Research Interests: Immunology, Argentina, Gene expression, HIV, Humans, and 15 moreGenetic Testing, Female, Frequency, Clinical Sciences, CIENCIAS DE LA SALUD, Adult, Enfermedades Infecciosas, Allele, Hypersensitivity, Abacavir, alleles, Gene frequency, Human leukocyte antigen, Drug hypersensitivity, and HIV infections
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Research Interests: Microbiology, Medical Microbiology, Virology, Medicine, HIV, and 11 moreDrug Resistance, Resistencia, Antimicrobial chemotherapy, Ciencias Biológicas, Genotyping, Antirretrovirales, Enseñanza - Aprendizaje Ciencias Naturales Y Exactas, Pediatría, Virología, Nevirapine, and Pharmacology and pharmaceutical sciences
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In Argentina, the human T-cell lymphotropic virus type 1 (HTLV-1) infection has been documented mainly among blood banks with a prevalence of ~0.02–0.046% for Buenos Aires city, 0.8% for the northeast, and 1% for the northwest; both areas... more
In Argentina, the human T-cell lymphotropic virus type 1 (HTLV-1) infection has been documented mainly among blood banks with a prevalence of ~0.02–0.046% for Buenos Aires city, 0.8% for the northeast, and 1% for the northwest; both areas are considered endemic for HTLV-2 and 1, respectively. Policies and specific guidelines for testing blood donors for HTLV are included since 2005. Screening for antibodies is performed at blood banks and confirmatory testing is performed at reference laboratories. There are no specific recommendations for the assistance of communities and individuals affected, nor referral to specialized clinics on the HTLV infection. In 2016, as a strategy of intervention, we opened a specialized clinical attendance in a referral infectious diseases public hospital for the comprehensive approach to patients with HTLV, offering follow-up and counseling for patients and their families for the early diagnosis of HTLV-1/2 and related diseases. During the study, 124 pa...
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HIV-1 determinants of coreceptor usage within the gp120 V3 loop have been broadly studied over the past years. This information has led to the development of state-of the-art bioinformatic tools that are useful to predict co-receptor... more
HIV-1 determinants of coreceptor usage within the gp120 V3 loop have been broadly studied over the past years. This information has led to the development of state-of the-art bioinformatic tools that are useful to predict co-receptor usage based on the V3 loop sequence mainly of subtypes B, C and A. However, these methods show a poor performance for subtype F V3 loops, which are found in an increasing number of HIV-1 strains worldwide. In the present work we investigated determinants of viral tropisms in the understudied subtype F by looking at genotypic and structural information of coreceptor:V3 loop interactions in a novel group of 40 subtype F V3 loops obtained from HIV-1 strains phenotypically characterized either as syncytium inducing or non-syncytium inducing by the MT-2 assay. We provide novel information about estimated interactions energies between a set of V3 loops with known tropism in subtype F, that allowed us to improve predictions of the coreceptor usage for this sub...
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Background: Although HIV-1 CRF12_BF and CRF38_BF are two epidemiologically important recombinant lineages circulating in Argentina and Uruguay, little is known about their population dynamics. Methods: A total of 120 “CRF12_BF-like ” and... more
Background: Although HIV-1 CRF12_BF and CRF38_BF are two epidemiologically important recombinant lineages circulating in Argentina and Uruguay, little is known about their population dynamics. Methods: A total of 120 “CRF12_BF-like ” and 20 “CRF38_BF-like ” pol recombinant sequences collected in Argentina and Uruguay from 1997 to 2009 were subjected to phylogenetic and Bayesian coalescent-based analyses to estimate evolutionary and demographic parameters. Results: Phylogenetic analyses revealed that CRF12_BF viruses from Argentina and Uruguay constitute a single epidemic with multiple genetic exchanges among countries; whereas circulation of the CRF38_BF seems to be confined to Uruguay. The mean estimated substitution rate of CRF12_BF at pol gene (2.5 × 10-3 substitutions/site/ year) was similar to that previously described for subtype B. According to our estimates, CRF12_BF and CRF38_BF originated at 1983 (1978-1988) and 1986 (1981-1990), respectively. After their emergence, the CR...
El abacavir (ABC) es un antirretroviral inhibidor de la transcriptasa reversa del virus HIV-1 que esta fuertemente asociado al desarrollo de reacciones de hipersensibilidad en individuos portadores del alelo HLA-B*5701. Objetivos:... more
El abacavir (ABC) es un antirretroviral inhibidor de la transcriptasa reversa del virus HIV-1 que esta fuertemente asociado al desarrollo de reacciones de hipersensibilidad en individuos portadores del alelo HLA-B*5701. Objetivos: determinar la prevalencia del alelo HLA-B*5701 en pacientes HIV-1 positivos y en una poblacion control de Argentina. Materiales y metodos: desde enero de 2012 hasta octubre de 2013 se estudiaron 869 pacientes HIV-1 positivos y 63 individuos no infectados con HIV-1. La deteccion del alelo HLA-B*5701 se realizo mediante un ensayo in house basado en la tecnica de PCR en tiempo real, disenado en nuestro laboratorio y validado segun guias internacionales. Resultados: el primero de enero se implemento el estudio farmacogenetico para la deteccion de hipersensibilidad al ABC en los pacientes incluidos en el Programa VIH/sida de la Direccion de SIDA y ETS, y en los ninos infectados con HIV-1 del Hospital Garrahan. Para ello se adopto un protocolo de envio, recepcio...
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Coronavirus disease 2019 (COVID-19) is spreading throughout the world. Limited data are available for the dynamics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral load (VL) in immunocompromised pediatric patients.... more
Coronavirus disease 2019 (COVID-19) is spreading throughout the world. Limited data are available for the dynamics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral load (VL) in immunocompromised pediatric patients. Here, we report the clinical characteristics and the dynamics of SARS-CoV-2 VL of a pediatric patient with acute myeloid leukemia who developed a hyperinflammatory status mimicked MIS-C. The clinical course was characterized by the late onset of fever, GI symptoms, rash, and respiratory distress, including oxygen requirement with sustained VL of SARS-CoV-2 around 7 log10 RNA copies/mL for 6 weeks. It is important to note that the hyperinflammatory status developed early at the third week of hospitalization—in a context of high VL and immunocompromised status. All these characteristics make this clinical case unique. On the other hand, while many reports have characterized the dynamics of SARS-CoV-2 VL in adults and immunocompetent hosts, it remains un...
I1 17th International Conference on Human Retroviruses: HTLV and Related Viruses, Trois Ilets, Martinique,(FWI). 18-21 June 2015 Raymond Cesaire, Agnès Lézin, Jean-Marie Péloponèse Jr Laboratoire de Virologie–Immunologie, EA 4537, Centre... more
I1 17th International Conference on Human Retroviruses: HTLV and Related Viruses, Trois Ilets, Martinique,(FWI). 18-21 June 2015 Raymond Cesaire, Agnès Lézin, Jean-Marie Péloponèse Jr Laboratoire de Virologie–Immunologie, EA 4537, Centre Hospitalier Universitaire de Fort-de-France, Fort-de-France, Martinique, France; Centre d’Études d’Agents Pathogènes et Biotechnologies pour la Santé, CNRS FRE 3689, Université Montpellier 1, Université Montpellier 2, Montpellier, France E-mail: jean-marie.peloponese@cpbs.cnrs.fr Retrovirology 2015, 12(Suppl 1):I1
There are gaps in understanding the causes and consequences of microcephaly. This paper describes the epidemiological characteristics, clinical presentations, and etiologies of children presenting microcephaly during the Zika outbreak in... more
There are gaps in understanding the causes and consequences of microcephaly. This paper describes the epidemiological characteristics, clinical presentations, and etiologies of children presenting microcephaly during the Zika outbreak in Argentina. This observational retrospective study conducted in the pediatric hospital of Juan P. Garrahan reviewed the medical records of 40 children presenting microcephaly between March 2017 and November 2019. The majority (60%) were males and born full-term. At first evaluation, microcephaly was defined as congenital (31/40, 77%) and associated with other features (68%) such as seizures, developmental delay, non-progressive chronic encephalopathy, and West Syndrome. It was found manifestations restricted to central nervous system (55%), ocular (8/40, 20%), and acoustic (9/40, 23%) defects, and abnormal neuroimaging findings (31/39, 79%). Non-infectious diseases were the primary cause of isolated microcephaly (21/37, 57%), largely related to genet...
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Background Current knowledge on HIV-1 resistance to integrase inhibitors (INIs) is based mostly on subtype B strains. This contrasts with the increasing use of INIs in low- and middle-income countries, where non-B subtypes predominate.... more
Background Current knowledge on HIV-1 resistance to integrase inhibitors (INIs) is based mostly on subtype B strains. This contrasts with the increasing use of INIs in low- and middle-income countries, where non-B subtypes predominate. Materials and methods HIV-1 drug resistance genotyping was performed in 30 HIV-1-infected individuals undergoing virological failure to raltegravir. Drug resistance mutations (DRMs) and HIV-1 subtype were characterized using Stanford HIVdb and phylogenetic analyses. Results Of the 30 integrase (IN) sequences, 14 were characterized as subtype F (47%), 8 as subtype B (27%), 7 as BF recombinants (23%) and 1 as a putative CRF05_DF (3%). In 25 cases (83%), protease and reverse transcriptase (PR-RT) sequences from the same individuals confirmed the presence of different BF recombinants. Stanford HIVdb genotyping was concordant with phylogenetic inference in 70% of IN and 60% of PR-RT sequences. INI DRMs differed between B and F IN subtypes, with Q148K/R/H, ...
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... Weijing He 1, 2 , Hemant Kulkarni 1, 2 , John Castiblanco 1, 2 , Chisato Shimizu 3 , Una Aluyen 1, 2 , Robert Maldonado 1, 2 , Andrew Carrillo 1, 2 , Madeline Griffin 1, 2 , Amanda Lipsitt 1, 2 , Lisa Beachy 1, 2 , Ludmila... more
... Weijing He 1, 2 , Hemant Kulkarni 1, 2 , John Castiblanco 1, 2 , Chisato Shimizu 3 , Una Aluyen 1, 2 , Robert Maldonado 1, 2 , Andrew Carrillo 1, 2 , Madeline Griffin 1, 2 , Amanda Lipsitt 1, 2 , Lisa Beachy 1, 2 , Ludmila Shostakovich-Koretskaya 4 , Andrea Mangano 5 , Luisa ...
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Post-infectious bronchiolitis obliterans (PIBO) is a severe disorder following acute lower pulmonary infection in young children, especially caused by adenovirus. Mannose-binding lectin (MBL) deficiency arising from polymorphisms in the... more
Post-infectious bronchiolitis obliterans (PIBO) is a severe disorder following acute lower pulmonary infection in young children, especially caused by adenovirus. Mannose-binding lectin (MBL) deficiency arising from polymorphisms in the coding and non-coding region on the MBL2 gene has been associated with more frequent and severe respiratory infections. Our aim was to evaluate the influence of MBL variants in the susceptibility and evolution of children with PIBO. One hundred eleven children with PIBO diagnosis were studied. The coding A, B, D and X promoter variants of MBL2 gene were assessed by PCR-RFLP. B and D alleles were pooled as O. The combined genotypes A/A and YA/O were grouped as sufficient MBL (sMBL), and O/O and XA/O as insufficient MBL (iMBL) groups. To evaluate the frequency of MBL2 polymorphisms in the general population, we studied DNA samples from 127 healthy donors from the blood bank of the hospital (control group). iMBL variants were significantly more frequent in PIBO children compared with controls (21.6% vs 10.2%, P = 0.01). PIBO patients with iMBL required intensive care unit (P = 0.001) and mechanical assistance at the moment of viral injury (P = 0.001) more frequently than those with sMBL. Insufficiency of MBL was more common in PIBO children than in healthy controls. This genetic condition was significantly associated with more severe initial disease, illustrating the relevance of innate immune defence factors prior to the maturation of the adaptative immune system.
Research Interests: Argentina, Adolescent, Disease susceptibility, Humans, Child, and 14 moreFemale, Inborn errors of metabolism, Male, Infant, Genotype, Respiratory Tract Infections, Genetic Polymorphism, Genetic variation, Bronchiolitis Obliterans, Respirology, Child preschool, Gene frequency, mannose binding lectin, and Medical and Health Sciences
HIV-1 diagnosis of perinatally exposed children is usually performed by molecular biology-based methods, allowing the direct detection of the virus. Thus, HIV-1 genomic variability within and across strains plays a major role in relation... more
HIV-1 diagnosis of perinatally exposed children is usually performed by molecular biology-based methods, allowing the direct detection of the virus. Thus, HIV-1 genomic variability within and across strains plays a major role in relation to the sensitivity of these tests, often leading to misdiagnosis. We describe the performance of an in-house multiplex nested PCR (nPCR) for early detection of HIV-1 infection in perinatally exposed children born in Argentina, where the percentage of diverse BF recombinants is as high as 80%. After evaluation of 1316 HIV-1 perinatally exposed children collected over a 7-year period, the specificity and sensitivity of the diagnostic nPCR was of 100% and 99.2% respectively, with only two false negative cases indicating a good performance of the diagnostic nPCR in the Argentine pediatric cohort. In search of unusual HIV-1 subtypes among 22 HIV-1 infected cases presenting partial or complete HIV-1 gene amplification failure, we performed phylogenetic an...
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The predominant circulating HIV-1 strains in South America are subtype B and B/F recombinants with different distributions among countries. However, the emergence of other subtypes is a matter of concern and needs continuous monitoring.... more
The predominant circulating HIV-1 strains in South America are subtype B and B/F recombinants with different distributions among countries. However, the emergence of other subtypes is a matter of concern and needs continuous monitoring. We identified three different A/G recombinants in Argentina, two of them in vertically infected children from unlinked mothers and one in an adult female. HIV-1 pol sequences from the children showed novel A/G recombination patterns and no phylogenetic relationship with previously reported South American A/G sequences. The third A/G recombinant was a CRF06_cpx with African origin. The detection of new or unusual subtypes is important to avoid false-negative PCR HIV-1 early diagnosis due to detection failures and for future vaccine development.
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Studies in humans and in experimental models of HIV-1 infection indicate an important role for monocyte chemoattractant protein-1 (MCP-1; also known as CC chemokine ligand 2), a potent chemoattractant and activator of mononuclear... more
Studies in humans and in experimental models of HIV-1 infection indicate an important role for monocyte chemoattractant protein-1 (MCP-1; also known as CC chemokine ligand 2), a potent chemoattractant and activator of mononuclear phagocytes (MP) in the pathogenesis of HIV-associated dementia (HAD). We determined the influence of genetic variation in MCP-1 on HIV-1 pathogenesis in large cohorts of HIV-1-infected adults and children. In adults, homozygosity for the MCP-1 -2578G allele was associated with a 50% reduction in the risk of acquiring HIV-1. However, once HIV-1 infection was established, this same MCP-1 genotype was associated with accelerated disease progression and a 4.5-fold increased risk of HAD. We examined the molecular and cellular basis for these genotype-phenotype associations and found that the mutant MCP-1 -2578G allele conferred greater transcriptional activity via differential DNA-protein interactions, enhanced protein production in vitro, increased serum MCP-1 ...
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Lipoprotein Lipase (LPL) is a key enzyme in lipid metabolism, especially for plasma triglycerides (TG). Genetic variants have been associated to lipid levels in healthy individuals, cardiovascular disease, obesity and diabetes. Our aim... more
Lipoprotein Lipase (LPL) is a key enzyme in lipid metabolism, especially for plasma triglycerides (TG). Genetic variants have been associated to lipid levels in healthy individuals, cardiovascular disease, obesity and diabetes. Our aim was to evaluate the influence of three polymorphisms: Hind III, Pvu II and S447X in plasma TG levels in Human Immunodeficiency Virus-1 (HIV-1) infected children under Highly Active Antiretroviral Therapy (HAART). 52 children diagnosed with HIV-1 between 2005 and 2009, were retrospectively selected with at least one plasma TG level assessment. TG levels were examined before and after one-year of HAART. Hypertriglyceridemia was defined as TG&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;150 mg/dL. Hind III (H+/H-), Pvu II (P+/P-) and S447X (S/X) were determined by PCR-RFLP. Wilcoxon sum rank test was used to compare median plasma TG among groups. Also, allelic frequencies were estimated for these variants in Argentinean population. Allelic frequencies for HIV-1 infected children were: H-, 0.21; P-, 0.53 and X, 0.05 with no significant differences to controls. After one-year of HAART, median TG levels were significantly lower in P-/P- (98.5 mg/dL) when compared to P+/P+ (180 mg/dL) (p=0.039). The presence of P- allele was associated with an 11-fold lower risk of hypertriglyceridemia. Hind III and S447X were not associated with TG at the selected time points. Our findings suggest a protective effect of LPL polymorphisms against hypertriglyceridemia in children after one-year HAART. These results could endorse a prompt nutritional or pharmacological intervention in patients lacking the P- allele.
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There is a considerable variation in the phenotype and course of the disease in cystic fibrosis (CF) even in patients with the same CFTR genotype, suggesting that other factors are important for prognosis. Mannose-binding lectin (MBL) has... more
There is a considerable variation in the phenotype and course of the disease in cystic fibrosis (CF) even in patients with the same CFTR genotype, suggesting that other factors are important for prognosis. Mannose-binding lectin (MBL) has been proposed as one of these factors. We therefore investigated the influence of MBL2 gene variants on disease severity, age at acquisition of Pseudomonas aeruginosa, and survival in CF patients. MBL2 variants were studied in 106 Argentinean pediatric CF patients carrying two severe CFTR mutations. Clinical phenotype was defined according to the Shwachman score and lung function tests. Age at infection with P. aeruginosa and age at death were also recorded. MBL insufficiency was associated with a 3.5-fold risk of having a severe phenotype (CI 95%: 1.2-10.3, p=0.03). It was also associated with an earlier onset of infection with P. aeruginosa (p=0.035). No statistically significant differences were found in FEV1 and survival. MBL insufficiency was ...