Ronaldo Celerino da Silva

Role of DC-SIGN and L-SIGN receptors in HIV-1 vertical transmission

Abstract The innate immune system acts in the first line of host defense against pathogens. One of the mechanisms used involves the early recognition and uptake of microbes by host professional phagocytes, through pattern recognition receptors (PRRs). These PRRs bind to conserved microbial ligands expressed by pathogens and initiate both innate and adaptative immune responses. Some PRRs located on the surface of dendritic cells (DCs) and other cells seem to play an important role in human immunodeficiency virus type 1 (HIV-1) transmission. Dendritic cell–specific intercellular adhesion molecule–3 grabbing non-integrin, CD209 (DC-SIGN) and its homolog, DC-SIGN-related (DC-SIGNR or L-SIGN) receptors are PPRs able to bind the HIV-1 gp120 envelope protein and, because alterations in their expression patterns also occur, they might play a role in both horizontal and vertical transmission as well as in disseminating the virus within the host. This review aims to explore the involvement of the DC-SIGN and L-SIGN receptors in HIV-1 transmission from mother to child.

MBL2 gene polymorphisms and susceptibility to tuberculosis in a northeastern Brazilian population

The innate immune system represents the first line of host defense against pathogens. Genetics factors regulating the immune responses play a role in the susceptibility to infectious diseases, such as tuberculosis (TB). We analyzed MBL2 promoter and exon 1 functional single nucleotide polymorphisms (SNPs) in a group of 155TB patients and 148 healthy controls in order to evaluate their influence on the onset of infection and TB development. There was no association between MBL2 -550 HL promoter polymorphisms and susceptibility to develop TB, but heterozygous -221 Y/X genotype was significantly more frequent in pulmonary TB patients than controls. Moreover, MBL2 exon 1 O allele, was significantly associated with susceptibility to TB development in general (p=0.023, OR=1.61, 95% CI 1.05-2.49) and pulmonary TB (p=0.0008, OR=2.16, 95% CI 1.35-3.46); C allele at codon 57, as well as A/C genotype, were significantly more frequent in TB patients than in controls. Our results indicate that MBL2 polymorphisms, especially at codon 57, could be considered as risk factors for TB development.

Host genomic HIV restriction factors modulate the response to dendritic cell-based treatment against HIV-1

Host genome is still poorly investigated in the context of vaccine or immunotherapy, however recently findings emphasized that it may affect the response to those treatments. In our retrospective study we evaluated the effect of HIV-1 genetic restriction factors on the response to dendritic cell (DC)-based immunotherapy in a Brazilian cohort of HIV positive (HIV+) patients that underwent a phase I clinical trial in 2004. Genomic DNA from 18 HIV+ individuals that underwent DC-based immunotherapy was analyzed for selected polymorphisms known to be associated with susceptibility to HIV-1 infection and/or AIDS progression. Allelic and genotypic distribution of the 22 polymorphisms was evaluated considering the response to the treatment. The rs11884476 SNP in PARD3B resulted associated with good response to immune treatment according to an over-dominant model. Even if functional effect of this variation is still unknown, our data suggested that it could play a role in the control of viral replication. Our findings, being aware of the limitation represented by the small number of subjects analyzed, suggest that genetic factors involved in AIDS progression could affect the response to immunotherapy, reinforcing the idea that deeper investigation on host genetic variations will be fundamental for a rational vaccine development.

Polymorphisms in DC-SIGN and L-SIGN genes are associated with HIV-1 vertical transmission in a Northeastern Brazilian population

DC-SIGN and L-SIGN are receptors expressed on specialized macrophages in decidua, (Hofbauer and placental capillary endothelial cells), known to interact with several pathogens, including HIV-1. To disclose the possible involvement of these molecules in the susceptibility to HIV vertical transmission, we analyzed DC-SIGN and L-SIGN gene single nucleotide polymorphisms (SNPs) in 192 HIV-1 positive children and 58 HIV-1 negative children all born to HIV-1 positive mothers, as well as 96 healthy uninfected children not exposed to HIV-1, all from Northeast Brazil. The frequency of three SNPs in the DC-SIGN promoter (-139G>A, -201G>T and -336A>G) were significantly different when comparing HIV positive children with HIV-1 exposed uninfected children, indicating an association with susceptibility to HIV-1 vertical transmission. This genetic association suggests that DC-SIGN molecule may play a role in susceptibility to HIV-1 infection through vertical transmission.

DEFB1 gene polymorphisms and tuberculosis in a Northeastern Brazilian population

β-Defensin-1, an antimicrobial peptide encoded by the DEFB1 gene, is known to play an important role in lung mucosal immunity. In our association study we analyzed three DEFB1 functional polymorphisms −52G>A (rs1799946), −44C>G (rs1800972) and −20G>A (rs11362) in 92 tuberculosis patients and 286 healthy controls, both from Northeast Brazil: no association was found between the studied DEFB1 polymorphisms and the disease. However we cannot exclude that this lack of association could be due to the low number of subjects analyzed, as suggested by the low statistical power achieved for the three analyzed SNPs (values between 0.16 and 0.50).

Dendritic Cell-Based Immunotherapies to Fight HIV: How Far from a Success Story? A Systematic Review and Meta-Analysis

The scientific community still faces the challenge of developing strategies to cure HIV-1. One of these pursued strategies is the development of immunotherapeutic vaccines based on dendritic cells (DCs), pulsed with the virus, that aim to boost HIV-1 specific immune response. We aimed to review DCs-based therapeutic vaccines reports and critically assess evidence to gain insights for the improvement of these strategies. We performed a systematic review, followed by meta-analysis and meta-regression, of clinical trial reports. Twelve studies were selected for meta-analysis. The experimental vaccines had low efficiency, with an overall success rate around 38% (95% confidence interval = 26.7%–51.3%). Protocols differed according to antigen choice, DC culture method, and doses, although multivariate analysis did not show an influence of any of them on overall success rate. The DC-based vaccines elicited at least some immunogenicity, that was sometimes associated with plasmatic viral load transient control. The protocols included both naïve and antiretroviral therapy (ART)-experienced individuals, and used different criteria for assessing vaccine efficacy. Although the vaccines did not work as expected, they are proof of concept that immune responses can be boosted against HIV-1. Protocol standardization and use of auxiliary approaches, such as latent HIV-1 reservoir activation and patient genomics are paramount for fine-tuning future HIV-1 cure strategies.

MAO‐B and COMT Genetic Variations Associated With Levodopa Treatment Response in Patients With Parkinson's Disease

The most commonly used Parkinsons disease (PD) treatment is the replacement of dopamine by its levodopa precursor (l‐dopa). Monoamine oxidase‐B (MAO‐B) and catechol‐o‐methyl transferase (COMT) are enzymes involved in the metabolism and regulation of dopamine availability. In our study we investigated the possible relation among selected single‐nucleotide polymorphisms (SNPs) in the MAO‐B (rs1799836) and COMT (rs4680) genes and the therapeutic response to levodopa (l‐dopa). A total of 162 Brazilian patients from the Pro‐Parkinson service of Clinics Hospital of Pernambuco diagnosed with sporadic PD and treated with levodopa were enrolled. PD patients were stratified into 2 groups according to the daily levodopa dose. MAO‐B and COMT SNP genotyping was conducted by polymerase chain reaction–restriction fragment length polymorphism. After multivariate analysis, we observed a significant difference between PD groups for the following variables: sex (P = .02), longer duration of disease (P = .02), longer levodopa therapy duration (P = .01), younger onset of PD (P = .01), and use of COMT inhibitor (P = .02). We observed that patients carrying MAO‐B (rs1799836) A and AA genotypes and COMT (rs4680) LL genotype suffered more frequently from levodopa‐induced‐dyskinesia. In addition, we found an increased risk of 2.84‐fold for male individuals carrying the MAO‐B G allele to be treated with higher doses of levodopa (P = .04). We concluded that before beginning PD pharmacological treatment, it is important to consider the genetic variants of the MAO‐B and COMT genes and the sex, reinforcing the evidence that sexual dimorphism in the genes related to dopamine metabolism might affect PD treatment.

Meta-Analysis and Time Series Modeling Allow a Systematic Review of Primary HIV-1 Drug-Resistant Prevalence in Latin America and Caribbean

Here we review the prevalence of HIV-1 primary drug resistance in Latin America and Caribbean using meta-analysis as well as time-series modeling. We also discuss whether there could be a drawback to HIV/AIDS programs due to drug resistance in Latin America and Caribbean in the next years. We observed that, although some studies report low or moderate primary drug resistance prevalence in Caribbean countries, this evidence needs to be updated. In other countries, such as Brazil and Argentina, the prevalence of drug resistance appears to be rising. Mutations conferring resistance against reverse transcriptase inhibitors were the most frequent in the analyzed populations (70% of all mutational events). HIV-1 subtype B was the most prevalent in Latin America and the Caribbean, although subtype C and B/F recombinants have significant contributions in Argentina and Brazil. Thus, we suggest that primary drug resistance in Latin America and the Caribbean could have been underestimated. Clinical monitoring should be improved to offer better therapy, reducing the risk for HIV-1 resistance emergence and spread, principally in vulnerable populations, such as men who have sex with men transmission group, sex workers and intravenous drug users.

DC-SIGN polymorphisms are associated to type 1 diabetes mellitus

Type I diabetes mellitus (T1DM) is an autoimmune disorder featured by raised glucoses levels. It has been hypothesised that raised glucose levels in T1DM might be recognised as PAMPs, leading to immune response by overloading the cell receptors for pathogens recognition. DC-SIGN is a transmembrane protein, present in dendritic cells (DC) and macrophages: it has an important role in inflammatory response and T cells activation. Notably, DC-SIGN activation and triggering of the immune response depend on the type of ligand, which may lead to a pro or anti-inflammatory pathway. In our association study, we analysed the SNPs rs4804803 (-336 A>G) and rs735239 (-871 A>G), both at DC-SIGN promoter region, in 210 T1DM patients and 157 healthy controls, also looking for a correlation with the age of onset of the disease. We found that the allele G and genotypes G/G and A/G of SNP-871 (rs735239), as well as the alleles G-G (rs735239-rs4804803) and genotypes combined AA-GG (rs735239-rs4804803) were associated with protection of T1DM development. We did not find association between these variations with the age of onset of the disease and the presence of other autoimmune disorders. Our results suggest that SNPs in DC-SIGN promoter region can be associated to protection for T1DM in the Northeast Brazilian population.

The influence of SLC6A3 and DRD2 polymorphisms on levodopa-therapy in patients with sporadic Parkinson's disease

The aim of this study was to evaluate a possible relationship between DRD2/ANKK1 (rs1800497) and SLC6A3/DAT1 (rs28363170) gene polymorphisms with the response to levodopa (L‐DOPA)‐therapy in patients with Parkinsons disease (PD).