Biomedical subjects

Marcelo A Soares

Publications and source records attributed to Marcelo A Soares.

At least 19 recordsLinked to original sources

PubMed2006

Characterization of a new circulating recombinant form comprising HIV-1 subtypes C and B in southern Brazil.

OBJECTIVE: To identify a new circulating recombinant form (CRF) of HIV-1 comprising two circulating subtypes in the southern region in Brazil, subtypes B and C. METHODS: A total of 152 HIV-positive patients followed at two hospitals in southern Brazil had their viral pol genes isolated by reverse transcriptase-polymerase chain reaction (PCR) from plasma. PCR products were sequenced and phylogenetically analysed using HIV-1 subtype reference sequences. Six full-length subtype C viruses from Brazil previously described as 'pure' strains were included in the analysis. Sequences suggestive of recombination were analysed by boot scanning and phylogenetic analyses of separate fragments. The common ancestry of recombinant strains was evaluated by similarity plot and informative site analyses. RESULTS: : HIV-1 subtypes commonly found in Brazil (B, C and F1) were observed. Sixty-two viruses were initially assigned as subtype C, but 15 viruses clustered in a separate internal clade. Pol from two full-length genomes of subtype C viruses grouped together with those samples. Boot scanning analysis showed that all 17 viruses had the same recombinant structure, with a 240 base pair fragment of subtype B in the middle of the reverse transcriptase pol region. Subtype B assignment of this fragment was confirmed by phylogenetic analyses using different methods of tree inference and cluster robustness tests. Mosaics were shown to have a common ancestry. CONCLUSION: As CRF_BC represents 11% of the HIV-1 viruses circulating in the southern region of the country, which borders several south American countries, the assessment of its spread is of pivotal importance to the HIV/AIDS epidemic in Brazil and Latin America.

Base Sequence↗

PubMed2006

DBCollHIV: a database system for collaborative HIV analysis in Brazil.

We developed a database system for collaborative HIV analysis (DBCollHIV) in Brazil. The main purpose of our DBCollHIV project was to develop an HIV-integrated database system with analytical bioinformatics tools that would support the needs of Brazilian research groups for data storage and sequence analysis. Whenever authorized by the principal investigator, this system also allows the integration of data from different studies and/or the release of the data to the general public. The development of a database that combines sequences associated with clinical/epidemiological data is difficult without the active support of interdisciplinary investigators. A functional database that securely stores data and helps the investigator to manipulate their sequences before publication would be an attractive tool for investigators depositing their data and collaborating with other groups. DBCollHIV allows investigators to manipulate their own datasets, as well as integrating molecular and clinical HIV data, in an innovative fashion.

Brazil↗

PubMed2006

Determinants of HIV-1 mother-to-child transmission in Southern Brazil.

Different human immunodeficiency virus type 1 (HIV-1) subtypes may have distinct biological, immunological and pathogenic properties. Efficiency of mother-to-child transmission (MTCT) may be among those properties, but few and controversial results have been described so far. In this study, 102 children born from HIV-1-infected mothers between 1998 and 2004 in the city of Rio Grande, Brazil were analyzed for potential risk factors associated with MTCT. That geographic region is characterized by a high proportion of subtype C-infected subjects, and it allowed comparison between subtypes B and C and their influence on MTCT. The analysis also included clinical, obstetric and immunological parameters. Multivariate regression analyses were conducted to evaluate the influence of the parameters on MTCT, and prevalence ratios (PR) and 95% confidence intervals (CI95) were also calculated. A surprisingly high prevalence of subtype C of over 70% was found. Only the HIV viral load and the use of ACTG 076 protocol were predictive of MTCT. HIV subtype and CD4 T-cell counts were not associated with increased risk of transmission. Although a clear expansion of subtype C is evident in southern Brazil, it does not seem to correlate with increased risk of vertical transmission.

Adult↗

PubMed2006

Biological characterization of human immunodeficiency virus type 1 subtype C protease carrying indinavir drug-resistance mutations.

Human immunodeficiency virus type 1 subtype C isolates belong to one of the most prevalent strains circulating worldwide and are responsible for the majority of new infections in the sub-Saharan region and other highly populated areas of the globe. In this work, the impact of drug-resistance mutations in the protease gene of subtype C viruses was analysed and compared with that of subtype B counterparts. A series of recombinant subtype C and B viruses was constructed carrying indinavir (IDV)-resistance mutations (M46V, I54V, V82A and L90M) and their susceptibility to six FDA-approved protease inhibitor compounds (amprenavir, indinavir, lopinavir, ritonavir, saquinavir and nelfinavir) was determined. A different impact of these mutations was found when nelfinavir and lopinavir were tested. The IDV drug-resistance mutations in the subtype C protease backbone were retained for a long period in culture without selective pressure when compared with those in subtype B counterparts in washout experiments.

Drug Resistance, Viral↗

PubMed2006

Discordances between interpretation algorithms for genotypic resistance to protease and reverse transcriptase inhibitors of human immunodeficiency virus are subtype dependent.

The major limitation of drug resistance genotyping for human immunodeficiency virus remains the interpretation of the results. We evaluated the concordance in predicting therapy response between four different interpretation algorithms (Rega 6.3, HIVDB-08/04, ANRS [07/04], and VGI 8.0). Sequences were gathered through a worldwide effort to establish a database of non-B subtype sequences, and demographic and clinical information about the patients was gathered. The most concordant results were found for nonnucleoside reverse transcriptase (RT) inhibitors (93%), followed by protease inhibitors (84%) and nucleoside RT inhibitor (NRTIs) (76%). For therapy-naive patients, for nelfinavir, especially for subtypes C and G, the discordances were driven mainly by the protease (PRO) mutational pattern 82I/V + 63P + 36I/V for subtype C and 82I + 63P + 36I + 20I for subtype G. Subtype F displayed more discordances for ritonavir in untreated patients due to the combined presence of PRO 20R and 10I/V. In therapy-experienced patients, subtype G displayed a lot of discordances for saquinavir and indinavir due to mutational patterns involving PRO 90 M and 82I. Subtype F had more discordance for nelfinavir attributable to the presence of PRO 88S and 82A + 54V. For the NRTIs lamivudine and emtricitabine, CRF01_AE had more discordances than subtype B due to the presence of RT mutational patterns 65R + 115 M and 118I + 215Y, respectively. Overall, the different algorithms agreed well on the level of resistance scored, but some of the discordances could be attributed to specific (subtype-dependent) combinations of mutations. It is not yet known whether therapy response is subtype dependent, but the advice given to clinicians based on a genotypic interpretation algorithm differs according to the subtype.

Algorithms↗

PubMed2005

Impact of HIV-1 subtype and antiretroviral therapy on protease and reverse transcriptase genotype: results of a global collaboration.

BACKGROUND: The genetic differences among HIV-1 subtypes may be critical to clinical management and drug resistance surveillance as antiretroviral treatment is expanded to regions of the world where diverse non-subtype-B viruses predominate. METHODS AND FINDINGS: To assess the impact of HIV-1 subtype and antiretroviral treatment on the distribution of mutations in protease and reverse transcriptase, a binomial response model using subtype and treatment as explanatory variables was used to analyze a large compiled dataset of non-subtype-B HIV-1 sequences. Non-subtype-B sequences from 3,686 persons with well characterized antiretroviral treatment histories were analyzed in comparison to subtype B sequences from 4,769 persons. The non-subtype-B sequences included 461 with subtype A, 1,185 with C, 331 with D, 245 with F, 293 with G, 513 with CRF01_AE, and 618 with CRF02_AG. Each of the 55 known subtype B drug-resistance mutations occurred in at least one non-B isolate, and 44 (80%) of these mutations were significantly associated with antiretroviral treatment in at least one non-B subtype. Conversely, of 67 mutations found to be associated with antiretroviral therapy in at least one non-B subtype, 61 were also associated with antiretroviral therapy in subtype B isolates. CONCLUSION: Global surveillance and genotypic assessment of drug resistance should focus primarily on the known subtype B drug-resistance mutations.

Amino Acid Sequence↗

PubMed2005

Different epidemic potentials of the HIV-1B and C subtypes.

HIV, the cause of AIDS in humans, is characterized by great genetic heterogeneity. In particular, HIV-1 group M subtypes are responsible for most of the infections worldwide. We investigate the demographic history of HIV-1B and HIV-1C subtypes in South Africa and Brazil using both a parametric and a nonparametric approach based on coalescent theory. Our results show that although both subtypes are spreading exponentially in Brazil, the HIV-1C growth rate is about twice that of Brazilian HIV-1B or South African HIV-1C, providing evidence, for the first time, of a different epidemic potential between two HIV-1 subtypes. The present study not only may have important consequences for devising future vaccination and therapeutic strategies, but also offers additional evidence that skyline plots are indeed a simple and powerful tool for monitoring and predicting the behavior of viral epidemics.

Acquired Immunodeficiency Syndrome↗

PubMed2005

HIV-1 subtype C dissemination in southern Brazil.

OBJECTIVES: To describe the molecular and epidemiological profile of HIV-1 in patients followed at the University Hospital of Rio Grande, Brazil. DESIGN AND METHODS: A cross-sectional study was conducted from September to December 2002. Plasma viral RNA of 85 patients was extracted and protease and reverse transcriptase genes were polymerase chain reaction-amplified and sequenced. Sequences were subtyped and examined to antiretroviral resistance mutations. Laboratory data and past history of antiretroviral treatment were also collected. RESULTS: Most viruses were either subtype B (42%) or subtype C (45%). No risk behaviour, sexual orientation or laboratory parameter was associated with any specific subtype, but subtype C tended to be more frequently found in women (P = 0.06). The prevalence of subtype C has increased over the HIV/AIDS epidemic, accounting for almost 60% of cases diagnosed in 2002. Intra-subtype genetic distances were smaller in subtype C than in subtype B, suggesting a more recent introduction of the former in the epidemic. Of patients under treatment, 60% had at least one antiretroviral drug resistance mutation, but no mutation was specifically associated with any HIV-1 subtype. Only one resistance mutation each was found in drug-naive patients with subtypes B and C. CONCLUSION: Despite the fact that subtype C appeared in southern Brazil more recently than subtype B, it is now the predominant strain in Rio Grande. The epidemic spread of subtype C could be taking place in Brazil, and possibly in south America, a phenomenon similar to that seen in other countries where this subtype is now totally dominant.

Adult↗

PubMed2005

Evolution of cyclophilin A and TRIMCyp retrotransposition in New World primates.

Host cell factors modulate retroviral infections. Among those, cyclophilin A (CypA) promotes virus infectivity by facilitating virus uncoating or capsid unfolding or by preventing retroviral capsid interaction with cellular restriction factors. In Aotus species, a retrotransposed copy of CypA inserted into the tripartite motif 5 (TRIM5) gene encodes a fusion protein which may block human immunodeficiency virus type 1 by targeting the incoming virus to ubiquitin-ligated degradation or by interfering with normal uncoating of the incoming particle, rendering those monkeys resistant to infection. In this study, we have extensively analyzed representative specimens from all New World primate genera and shown that the retrotransposed CypA copy is only present in Aotus. We have shown that this inserted copy diverged from its original counterpart and that this occurred prior to Aotus radiation, although no positive selection was observed. Finally, our data underscores the need for a precise taxonomic identification of primate species used as models for retroviral infections and novel antiviral approaches.

Animals↗

PubMed2004

CCR5 chemokine receptor gene evolution in New World monkeys (Platyrrhini, Primates): implication on resistance to lentiviruses.

The CC chemokine receptor 5 (CCR5) gene of primates encodes a transmembrane protein involved in cellular signaling of some cell types of the immune system. Numerous studies have shown that this peptide is used by lentiviruses in conjunction with the CD4 receptor to mediate binding and entry in target cells of human and non-human primates. New World monkeys (NWM), differently from their African counterparts, have no description of in natura lentivirus infection. Some evidences suggest that a blockage occurs at the viral entry step of infection. To investigate this possibility, we have cloned and sequenced CCR5 genes from several representatives of Platyrrhini, and compared their sequences with those of other Platyrrhini and Catarrhini species available at public databases. Platyrrhini CCR5 genes were shown to be more genetically diverse than their Catarrhini correlates, and their phylogenetic relationships based on that locus were in agreement with previous studies. Comparison of Platyrrhini and Catarrhini CCR5 consensus sequences evidenced several amino acid residues that differ between both groups, some of which have been experimentally associated with lentiviral interaction. A codon-based positive selection analysis showed that some of these sites seem to be under strong selection for variation among the Platyrrhini but not among Catarrhini species. These results suggest the potential involvement of those sites in the apparent refraction of some NWM to lentiviruses. The high ccr5 genetic diversity observed in Platyrrhini, however, argues for a more extensive infection analysis of diverse NWM species to evaluate this resistance and the potential use of those primates as HIV/AIDS animal models.

Adaptation, Physiological↗

PubMed2004

Overview of genotypic and clinical profiles of human immunodeficiency virus type 1-infected children in Rio de Janeiro, Brazil.

Although mother-to-child HIV transmission prevention has slowed down pediatric HIV infection in developed countries, large numbers of infants still become infected in developing nations. Data on pediatric HIV infection is however largely scarce. In this study, we have overviewed clinical, laboratory and genotypic data from a large cohort of HIV-infected infants regularly followed at two pediatric HIV outpatient clinics in Rio de Janeiro, Brazil. Children on antiretroviral therapy, as well as drug-naive, newly diagnosed infants were analyzed. Prevalence of drug resistance mutations, as well as immunological and virological responses to therapy were evaluated. Additionally, HIV-1 subtype frequencies and their distribution over the course of the epidemic were studied. We have found a high prevalence of mutations among ARV-experienced children, whereas mutations were absent in the drug-naive group. Despite the high levels of resistance among treated infants, an important improvement of their immunological status was observed. HIV-1 subtype distribution followed the trends of the adult population, with the appearance of non-B subtypes and recombinant forms after 1990. To our knowledge, this is the largest pediatric cohort ever analyzed in Brazil, and the data provided is of paramount importance to a better understanding of HIV/AIDS evolution in pediatric settings.

Adolescent↗

PubMed2004

Synonymous genetic polymorphisms within Brazilian human immunodeficiency virus Type 1 subtypes may influence mutational routes to drug resistance.

BACKGROUND: Most published data on antiretroviral-drug resistance is generated from in vitro or in vivo studies of subtype B virus. However, this subtype is associated with <10% of HIV infections worldwide, and it is essential to explore subtype-specific determinants of drug resistance. One potential cause of the differences between subtypes is the synonymous codon usage at key resistance positions. METHODS: We investigated the nucleotide sequences at drug resistance-related sites, for all major Brazilian subtypes (B, C, and F1) of human immunodeficiency virus type 1 (HIV-1) group M. RESULTS: We identified a change at positions 151 and 210 of the reverse-transcriptase region in subtype F1, such that the emergence of these key nucleoside/nucleotide analogue resistance mutations required an extra nucleotide change in subtype F1, compared with subtypes B and C. The clinical significance of position 210 was confirmed within a large Brazilian database, in which we identified a lower prevalence of the L210W mutation in subtype F1 virus, compared with subtype B virus, in patients matched for thymidine-analogue experience. An inverse relationship between the L210W and K70R mutations was also observed. CONCLUSIONS: The findings of the present study illustrate an important mechanism by which a subtype may determine genetic routes to resistance, with implications for treatment strategies for populations infected with HIV-1 subtype F.

Base Sequence↗

PubMed2004

Primary HIV-1 drug resistance in Brazil.

In this report we reviewed primary HIV-1 drug resistance in Brazil and compared it with that of other developed countries. An extensive survey was conducted in published studies on primary HIV-1 drug resistance in Brazil and in several developed countries in North America and Western Europe. Overall and genomic region-specific (protease or reverse transcriptase) rates were compared between countries and over time in some countries (whenever available) to detect their trend over time and in different groups of individuals (acutely or chronically infected patients). Brazil has shown primary drug resistance rates that were on average lower than in most developed countries analysed. There were no reports in Brazil showing the occurrence of multidrug-resistant HIV-1 strains circulating in drug-naive patients, in contrast to some countries. Rates of protease secondary mutations observed in Rio de Janeiro (the second largest city affected by the HIV/AIDS epidemic in Brazil) did not show evidence of increase, but rather mutation-specific steady state equilibria. Despite the universal access to antiretroviral treatment in the country, rates of primary drug resistance are still low when compared with those of developed nations, arguing against the need for genotyping in patients before initiating therapy. The lower rates of primary drug resistance reported show that resistance should not be of concern in promoting expanded access to antiretroviral treatment in developing settings.

Brazil↗

PubMed2004

Alternative, age- and viral load-related routes of nelfinavir resistance in human immunodeficiency virus type 1-infected children receiving highly active antiretroviral therapy.

To assess prevalence of nelfinavir resistance mutations in children receiving highly active antiretroviral therapy, sequencing of protease gene from plasma of 53 human immunodeficiency virus-infected children was performed. The prevalence of L90M was similar to that of D30N. There was a significant correlation with a higher viral load and lower age and the occurrence of L90M. These findings suggest differential molecular age- and viral load-related routes for nelfinavir resistance.

Age Factors↗

PubMed2004

Impact of nelfinavir resistance mutations on in vitro phenotype, fitness, and replication capacity of human immunodeficiency virus type 1 with subtype B and C proteases.

Human immunodeficiency virus type 1 subtype B and C proteases were manipulated to contain 90M, 88D, or 89L, and their in vitro biological properties were studied. We showed that D30N has significantly more impact in subtype C than in subtype B counterparts, accounting for the reported low prevalence of this mutation in patients failing nelfinavir-based regimens.

Cell Line↗

PubMed2004

Prevalence of human immunodeficiency virus drug resistance mutations and subtypes in drug-naive, infected individuals in the army health service of Rio de Janeiro, Brazil.

The prevalence of mutations that confer resistance to antiretroviral drugs was examined in 56 drug-naive, human immunodeficiency virus type 1 (HIV-1)-infected individuals from the Army Health Service in Rio de Janeiro, Brazil. No primary protease inhibitor mutations were found, but secondary mutations were observed in 51.2% of the samples. Fourteen percent of the viruses had reverse transcriptase inhibitor-associated mutations. Comparative analysis of protease secondary mutations from four different time periods in drug-naive patients in the city of Rio de Janeiro has indicated constant rates for particular mutations. Changes in CD4 cell counts and HIV viral load over time in subtype B- and non-B-infected drug-naive patients were not significantly different.

Acquired Immunodeficiency Syndrome↗

PubMed2004

DC-SIGN from African green monkeys is expressed in lymph nodes and mediates infection in trans of simian immunodeficiency virus SIVagm.

African green monkeys (AGMs) infected by simian immunodeficiency virus (SIV) SIVagm are resistant to AIDS. SIVagm-infected AGMs exhibit levels of viremia similar to those described during pathogenic human immunodeficiency virus type 1 (HIV-1) and SIVmac infections in humans and macaques, respectively, but contain lower viral loads in their lymph nodes. We addressed the potential role of dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin (DC-SIGN; CD209) in viral dissemination. In previous studies, it has been shown that human DC-SIGN and macaque DC-SIGN allow transmission of HIV and SIVmac to T cells. Here, we looked at the ability of DC-SIGN derived from AGM lymph nodes to interact with SIVagm. We show that DC-SIGN-expressing cells are present mainly in the medulla and often within the cortex and/or paracortex of AGM lymph nodes. We describe the isolation and characterization of at least three isoforms of dc-sign mRNA in lymph nodes of AGMs. The predicted amino acid sequence from the predominant mRNA isoform, DC-SIGNagm1, is 92 and 99% identical to the corresponding human and rhesus macaque DC-SIGN amino acid sequences, respectively. DC-SIGNagm1 is characterized by the lack of the fourth motif in the repeat domain. This deletion was also detected in the dc-sign gene derived from thirteen animals belonging to five other African monkey species and from four macaques (Macaca fascicularis and M. mulatta). Despite three- to seven-amino-acid modifications compared to DC-SIGNmac, DC-SIGNagm1 allows transmission of SIVagm to T cells. Furthermore, AGM monocyte-derived dendritic cells (MDDC) expressed at least 100,000 DC-SIGN molecules and were able to transmit SIVagm to T cells. At a low multiplicity of infection (10(-5) 50% tissue culture infective doses/cell), viral transmission by AGM MDDC was mainly DC-SIGN dependent. The present study reveals that DC-SIGN from a natural host species of SIV has the ability to act as an efficient attachment and transmission factor for SIVagm and suggests the absence of a direct link between this ability and viral load levels in lymph nodes.

Amino Acid Sequence↗

PubMed2003

Epidemiologic and molecular characterization of human immunodeficiency virus type 1 in southern Brazil.

HIV subtype C is the most prevalent subtype in the world. Despite its recent expansion in Brazil, HIV-1C already prevails in the southernmost state of Brazil, Rio Grande do Sul. This unique HIV epidemiology has prompted us to characterize that population. Seventy-seven HIV-1-infected subjects attending the largest HIV/AIDS clinic of the state had the protease and reverse transcriptase (RT) genes of their virus subtyped and genotyped. When subtype-specific infections were plotted according to year of diagnosis, the prevalence of subtype C was shown to increase over the last 18 years of the epidemic, along with a concomitant decrease of subtype B. Comparison of subtype C-infected treated and untreated subjects revealed amino acid differences in protease and RT, especially in the RT mutation D/G123S. The overall analysis of drug resistance mutations in viruses from treated subjects has highlighted some associations between subtypes and particular mutations, such as V82A/F/T/S in protease and subtype F1 and M41L and L210W in RT and subtype B. The characterization of this important population, which is one of a few in the developing world where a large number of HIV-1C-infected subjects are under antiretroviral treatment, underscores its potential usefulness in clinical, treatment, and vaccine trials in Brazil.

Acquired Immunodeficiency Syndrome↗