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De Maio F.A.,CONICET | Rocco C.A.,CONICET | Aulicino P.C.,CONICET | Bologna R.,Servicio de Epidemiologia e Infectologia | And 2 more authors.
AIDS Research and Human Retroviruses | Year: 2012

The APOBEC3 proteins are cytidine deaminases that can introduce G→A mutations in the HIV-1 plus DNA strand. This editing process may inhibit virus replication through lethal mutagenesis (hypermutation), but could also contribute to viral diversification leading to the emergence of escape forms. The HIV-1 Vif protein has the capacity to counteract APOBEC3 factors by recruiting a CUL5-based ubiquitin ligase complex that determines their proteasomal degradation. In this work, we analyzed the APOBEC3-mediated editing in proviral HIV-1 from perinatally infected children (n=93) in order to explore its association with polymorphisms of APOBEC3G and CUL5 genes (APOBEC3G H186R, APOBEC3G C40693T, and CUL5 SNP6), the Vif protein variability, and also the time to AIDS development. To calculate the level of editing, we have developed an index exploiting the properties of a region within the HIV-1 pol gene that includes the central polypurine tract (cPPT). We detected a reduced editing associated with the CUL5 SNP6 minor allele and also with certain Vif variants (mutations at sites 46, 122, and 160), although we found no evidence supporting an impact of APOBEC3 activity on disease progression. Thus, our findings suggest that APOBEC3-mediated editing of HIV-1 could be modulated by host and virus genetic characteristics in the context of pediatric infection. © Copyright 2012, Mary Ann Liebert, Inc. Source


De Maio F.A.,CONICET | Rocco C.A.,CONICET | Aulicino P.C.,CONICET | Bologna R.,Servicio de Epidemiologia e Infectologia | And 2 more authors.
Infection, Genetics and Evolution | Year: 2011

The APOBEC3G protein is a restriction factor that can inhibit the replication of HIV-1. The virus has the capacity to counteract this antiviral activity through the expression of the Vif accessory protein, which recruits a CUL5-based ubiquitin ligase complex that determines APOBEC3G proteasomal degradation. In this work we evaluated in a large pediatric cohort (i) whether single nucleotide polymorphisms of APOBEC3G and CUL5 genes (APOBEC3G H186R, APOBEC3G C40693T and CUL5 SNP6) can alter the risk of HIV-1 vertical transmission and/or the rate of progression to AIDS, (ii) the effect of HIV-1 Vif variants on the clinical course of disease, and (iii) whether the patient genotype for the studied polymorphisms could have an impact on Vif characteristics.We found no effect of the studied APOBEC3G or CUL5 genetic variants on vertical transmission or progression to pediatric AIDS. However, we detected an association of certain Vif alterations (a one amino acid insertion at position 61 and the substitutions A62D/N/S and Q136P) with an accelerated AIDS outcome. Additionally, we observed that the APOBEC3G C40693T and CUL5 SNP6 minor alleles were correlated with substitutions in Vif motifs that are involved in the interaction with APOBEC3G and CUL5 proteins, respectively. Our results suggest that Vif alterations may contribute to a rapid AIDS onset and that Vif variability could be influenced by APOBEC3G and CUL5 polymorphisms in children. © 2011 Elsevier B.V. Source


Fernandez M.F.,CONICET | Golemba M.D.,CONICET | Terrones C.,Hospital Carlos G. Durand | Paradiso P.,Hospital Carlos G. Durand | And 5 more authors.
AIDS Research and Human Retroviruses | Year: 2015

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. © Mary Ann Liebert, Inc. Source


Ruvinsky S.,Servicio de Epidemiologia e Infectologia | Rowenstein H.,Servicio de Clinica Medica | Taicz M.,Servicio de Epidemiologia e Infectologia | Paolillo A.,Servicio de Epidemiologia e Infectologia | And 5 more authors.
Revista Chilena de Infectologia | Year: 2013

Tuberculosis is an important public health problem. It is estimated that around 5-10% of patients with tuberculosis present with central nervous system involvement; meningitis and tuberculoma being two of the most frequent manifestations. The paradoxical reaction in patients undergoing antituberculosis treatment is infrequent, nevertheless it is an important consideration in patients, who after an appropriate initial response to specific treatment, present with worsening clinical and radiological signs or the appearance of new lesions. Source


Bellusci C.P.,CONICET | Rocco C.,CONICET | Aulicino P.,CONICET | Mecikovsky D.,Servicio de Epidemiologia e Infectologia | And 6 more authors.
Gene | Year: 2013

Background: Variability in MDR1 and PXR has been associated with differences in drug plasma levels and response to antiretroviral therapy. We investigated whether polymorphisms in MDR1 (T-129C, C1236T and C3435T) and PXR (C63396T) affect lopinavir plasma concentration and the virological or immunological response to HAART in HIV-1-infected children. Methods: Genotypes were identified in 100 blood donors and 38 HIV-1-infected children. All children received HAART with lopinavir boosted with ritonavir (LPV/r) at the time of LPV plasma level quantification, before (Ctrough) and between 1 and 2h after (Cpost-dose) the administration of the next dose of drug. CD4+ T-cell counts and plasma viral load were analyzed before and after the initiation of LPV/r. Results: MDR1 1236T, MDR1 3435T and PXR 63396T alleles showed a frequency of ~50% while the MDR1 -129C allele only reached 5%. Children heterozygotes 1236CT showed a significantly lower LPV Cpost-dose than homozygotes 1236TT (median Cpost-dose=3.04μg/ml and 6.50μg/ml, respectively; p=0.016). Children heterozygotes 1236CT also had a lower decrease of viral load after 36weeks of LPV/r exposure compared with homozygotes 1236CC (median viral load changes=-0.50log10 copies/ml and -2.08log10 copies/ml, respectively; p=0.047). No effect on the immunological response was observed for polymorphisms of MDR1 or PXR. Conclusions: Our results suggest that the MDR1 C1236T SNP significantly reduces LPV plasma concentration affecting the virological response to HAART. Heterozygotes 1236CT might have an altered level of P-gp expression/activity in enterocytes and CD4+ T lymphocytes that limits the absorption of LPV leading to an impaired virological suppression. © 2013 Elsevier B.V. Source

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