Recombination confounds the early evolutionary history of human immunodeficiency virus type 1: Subtype G is a circulating recombinant form

Human immunodeficiency virus type I (HIV-1) is classified in nine subtypes (A to D, F, G, H, J, and K), a number of subsubtypes, and several circulating recombinant forms (CRFs). Due to the high level of genetic diversity within HIV-1 and to its worldwide distribution, this classification system is widely used in fields as diverse as vaccine development, evolution, epidemiology, viral fitness, and drug resistance. Here, we demonstrate how the high recombination rates of HIV-1 may confound the study of its evolutionary history and classification. Our data show that subtype G, currently classified as a pure subtype, has in fact a recombinant history, having evolved following recombination between subtypes A and J and a putative subtype G parent. In addition, we find no evidence for recombination within one of the lineages currently classified as a CRF, CRF02 -AG. Our analysis indicates that CRF02_AG was the parent of the recombinant subtype G, rather than the two having the opposite evolutionary relationship, as is currently proposed. Our results imply that the current classification of HIV-1 subtypes and CRFs is an artifact of sampling history, rather than reflecting the evolutionary history of the virus. We suggest a reanalysis of all pure subtypes and CRFs in order to better understand how high rates of recombination have influenced HIV-1 evolutionary history.</p

inTB - a data integration platform for molecular and clinical epidemiological analysis of tuberculosis

This deposit is composed by the main article plus the supplementary materials of the publication.Tuberculosis is currently the second highest cause of death from infectious diseases worldwide. The emergence of multi and extensive drug resistance is threatening to make tuberculosis incurable. There is growing evidence that the genetic diversity of Mycobacterium tuberculosis may have important clinical consequences. Therefore, combining genetic, clinical and socio-demographic data is critical to understand the epidemiology of this infectious disease, and how virulence and other phenotypic traits evolve over time. This requires dedicated bioinformatics platforms, capable of integrating and enabling analyses of this heterogeneous data.Instituto Gulbenkian de Ciência, Programa Nacional de Luta contra a Tuberculose, Instituto Nacional de Saúde Ricardo Jorge, Administração Regional de Saúde de Lisboa e Vale do Tejo

Effect of Natural Polymorphisms in the HIV-1 CRF02_AG Protease on Protease Inhibitor Hypersusceptibility

Hypersusceptibility (HS) to inhibition by different antiretroviral drugs (ARVs) among diverse HIV-infected individuals may be a misnomer because clinical response to treatment is evaluated in relation to subtype B infections while drug susceptibility of the infecting virus, regardless of subtype, is compared to a subtype B HIV-1 laboratory strain (NL4-3 or IIIB). Mounting evidence suggests that HS to different ARVs may result in better treatment outcome just as drug resistance leads to treatment failure. We have identified key amino acid polymorphisms in the protease coding region of a non-B HIV-1 subtype linked to protease inhibitor HS, namely, 17E and 64M in CRF02_AG. These HS-linked polymorphisms were introduced in the BD6-15 CRF02_AG molecular clone and tested for inhibition using a panel of protease inhibitors. in general, suspected HS-linked polymorphisms did increase susceptibility to specific protease inhibitors such as amprenavir and atazanavir, but the combination of the 17E/64M polymorphisms showed greater HS. These two mutations were found at low frequencies but linked in a sequence database of over 700 protease sequences of CRF02_AG. in direct head-to-head virus competitions, CRF02_AG harboring the 17E/64M polymorphisms also had higher replicative fitness than did the 17E or the 64M polymorphism in the CFR02_AG clone. These findings suggest that subtype-specific, linked polymorphisms can result in hypersusceptibility to ARVs. Considering the potential benefit of HS to treatment outcome, screening for potential HS-linked polymorphisms as well as preexisting drug resistance mutations in treatment-naive patients may guide the choice of ARVs for the best treatment outcome.Case Western Reserve Univ, Cleveland, OH 44106 USAUniv Fed Rio de Janeiro, Dept Genet, Lab Virol Humana, Rio de Janeiro, BrazilHosp Egas Moniz, Lisbon, PortugalUniversidade Federal de São Paulo, Lab Retrovirol, São Paulo, BrazilUniv Rostock, Rostock, GermanyInst Nacl Canc, Programa Genet, Rio de Janeiro, BrazilUniversidade Federal de São Paulo, Lab Retrovirol, São Paulo, BrazilWeb of Scienc

Genetic lineage characterization and spatiotemporal dynamics of the recently established Brevihamaparvovirus genus

Copyright © 2022 Elsevier B.V. All rights reserved.The analysis of the viruses allocated to the recently established Brevihamaparvovirus genus (Parvoviridae family), which includes all previously known brevidensoviruses, has not yet been carried out on an extensive basis. As a result, no detailed genetic lineage characterization has ever been performed for this group of insect-specific viruses. Using a wide range of molecular tools, we have explored this taxon by calculating Shannon entropy values, intra- and inter-taxon genetic distances, analysed sequence polymorphisms, and evaluated selective pressures acting on the viral genome. While the calculated Brevihamaparvovirus mutation rates were within the range of those of other parvoviruses, their genomes look to be under strong purifying selection, and are also characterized by low diversity and entropy. Furthermore, even though recombination events are quite common among parvoviruses, no evidence of recombination (either intra or intergenic) was found in the Brevihamaparvoviruses sequences analyzed. An extended taxonomic analysis and reevaluation of existing Brevihamaparvoviruses sequences, many still unclassified, was performed using cut-off values defining NS1 identity between viral sequences from the Parvovirus family. Two existing genetic lineages, Dipteran Brevihamaparvovirus 1 and Dipteran Brevihamaparvovirus 2, were rearranged and the creation of a new one, Dipteran Brevihamaparvovirus 3, was suggested. Finally, despite the uncertainties associated with both the time estimates of the most recent common ancestors, which could span from twenty thousand years before the current era to way earlier (in the last century), and the dispersal routes proposed for Brevihamaparvoviruses sequences by phylodynamic reconstruction, the analyses here presented could help define how future studies should be conducted as more isolates continue to be identified in the future, and contribute to eliminating possible analytical biases.publishersversionpublishe

Readdressing the genetic diversity and taxonomy of the Mesoniviridae family, as well as its relationships with other nidoviruses and putative mesonivirus-like viral sequences

Copyright © 2022 Elsevier B.V. All rights reserved.Research on the recently established Mesoniviridae family (Order Nidovirales), RNA genome insect-specific viruses, has been steadily growing in the last decade. However, after the last detailed phylogenetic characterization of mesoniviruses in 2014, numerous new sequences, even in organisms other than mosquitos, have been identified and characterized. In this study, we analyzed nucleotide and protein sequences of mesoniviruses with a wide range of molecular tools including genetic distance, Shannon entropy, selective pressure analysis, polymorphism identification, principal coordinate analysis, likelihood mapping and phylodynamic reconstruction. We also sought to revaluate new mesoniviruses sequence positions within the family, proposing a taxonomic revision. The different sub-lineages of mosquito mesoniviruses sequences presented low sequence diversity and entropy, with incongruences to the existing taxonomy being found after an extensive phylogenetic characterization. High sequence discrepancy and differences in genome organization were found between mosquito mesoniviruses and other mesoniviruses, so their future classification, as other meso-like viruses that are found in other organisms, should be approached with caution. No evidence of frequent recombination was found, and mesonivirus genomes seem to evolve under strong purifying selection. Insufficient data by root-to-tip analysis did not yet allow for an adequate phylogeographic reconstruction.publishersversionpublishe

Spectrum of Non-Nucleoside Reverse Transcriptase Inhibitor-Associated Drug Resistance Mutations in Persons Living with HIV-1 Receiving Rilpivirine

Funding Information: This work was funded by a grant from the National Institutes of Health: 2R24AI13661806. The funder played no role in this review. Publisher Copyright: © 2024 by the authors.Introduction: Few data are currently available on the nonnucleoside reverse transcriptase (RT) inhibitors (NNRTI) resistance mutations selected in persons living with HIV-1 (PLWH) who develop virological failure while receiving rilpivirine (RPV). Methods: We analyzed pooled HIV-1 RT genotypic data from 280 PLWH in the multicenter EuResist database and 115 PLWH in the Stanford HIV Drug Resistance Database (HIVDB) who received RPV as their only NNRTI. Results: Among the 395 PLWH receiving RPV, 180 (45.6%) had one or more NNRTI-associated DRMs. Overall, 44 NNRTI-associated DRMs were identified, including 26 that occurred in two or more PLWHs. Seven mutations had a prevalence ≥10% among the 180 PLWH with one or more NNRTI-associated DRM: E138K (32.2%), V90I (25.0%), K101E (17.8%), Y181C (17.2%), E138A (13.9%), H221Y (12.2%), and K103N (10.6%). Y181C was significantly more likely to co-occur with K101E, V179F, H221Y, and M230L. Ten novel non-polymorphic mutations at known NNRTI-associated mutation positions were also identified, usually in just one PLWH: L100F, V108A, T139I, P225S, M230V, Y232C, and T240A/I/M/S. Conclusions: Our analysis extends the spectrum of mutations emerging in PLWH receiving RPV. Additional phenotypic characterization of RPV-selected mutations is necessary to better understand their biological and possible clinical significance.publishersversionpublishe

Increase in transmitted resistance to non-nucleoside reverse transcriptase inhibitors among newly diagnosed HIV-1 infections in Europe

Background: One out of ten newly diagnosed patients in Europe was infected with a virus carrying a drug resistant mutation. We analysed the patterns over time for transmitted drug resistance mutations (TDRM) using data from the European Spread program.Methods: Clinical, epidemiological and virological data from 4317 patients newly diagnosed with HIV-1 infection between 2002 and 2007 were analysed. Patients were enrolled using a pre-defined sampling strategy.Results: The overall prevalence of TDRM in this period was 8.9% (95% CI: 8.1-9.8). Interestingly, significant changes over time in TDRM caused by the different drug classes were found. Whereas nucleoside resistance mutations remained constant at 5%, a significant decline in protease inhibitors resistance mutations was observed, from 3.9% in 2002 to 1.6% in 2007 (p = 0.001). In contrast, resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs) doubled from 2.0% in 2002 to 4.1% in 2007 (p = 0.004) with 58% of viral strains carrying a K103N mutation. Phylogenetic analysis showed that these temporal changes could not be explained by large clusters of TDRM.Conclusion: During the years 2002 to 2007 transmitted resistance to NNRTI has doubled to 4% in Europe. The frequent use of NNRTI in first-line regimens and the clinical impact of NNRTI mutations warrants continued monitoring

Patterns of transmitted HIV drug resistance in Europe vary by risk group

Background: In Europe, a continuous programme (SPREAD) has been in place for ten years to study transmission of drug resistant HIV. We analysed time trends of transmitted drug resistance mutations (TDRM) in relation to the risk behaviour reported. Methods: HIV-1 patients newly diagnosed in 27 countries from 2002 through 2007 were included. Inclusion was representative for risk group and geographical distribution in the participating countries in Europe. Trends over time were calculated by logistic regression. Results: From the 4317 patients included, the majority was men-having-sex-with-men -MSM (2084, 48%), followed by heterosexuals (1501, 35%) and injection drug users (IDU) (355, 8%). MSM were more often from Western Europe origin, infected with subtype B virus, and recently infected (<1 year) (p<0.001). The prevalence of TDRM was highest in MSM (prevalence of 11.1%), followed by heterosexuals (6.6%) and IDU (5.1%, p<0.001). TDRM was predominantly ascribed to nucleoside reverse transcriptase inhibitors (NRTI) with a prevalence of 6.6% in MSM, 3.3% in heterosexuals and 2.0% in IDU (p = 0.001). A significant increase in resistance to non- nucleoside reverse transcriptase inhibitors (NNRTIs) and a decrease in resistance to protease inhibitors was observed in MSM (p = 0.008 and p = 0.006, respectively), but not in heterosexual patients (p = 0.68 and p = 0.14, respectively). Conclusions: MSM showed to have significantly higher TDRM prevalence compared to heterosexuals and IDU. The increasing NNRTI resistance in MSM is likely to negatively influence the therapy response of first-line therapy, as most include NNRTI drugs

A Comparative Proteomic Analysis of Praziquantel-Susceptible and Praziquantel-Resistant Schistosoma mansoni Reveals Distinct Response Between Male and Female Animals

Funding Information: We acknowledge the Mass Spectrometry Laboratory at Brazilian Biosciences National Laboratory, CNPEM, Campinas, Brazil for their support with the mass spectrometry analysis. The authors would like to thank Professor Ana Tomás from IBMC and GABBA program (Porto, Portugal), for very helpful suggestions that improved greatly this paper. Funding Information: This work was initially supported by Fundação para a Ciência e a Tecnologia de Portugal (FCT) by grant PEst-OE/SAU/UI0074/2014. AP-A was initially funded by Graduate Program in Areas of Basic and Applied Biology (GABBA) from the Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto and FCT (SFRH/BD/51697/2011) meanwhile received the António Coutinho Science Award (11/BI-PD/20) by the Instituto Gulbenkian de Ciência (IGC) of the Fundação Calouste Gulbenkian, and Fundação Familia Merk and Câmara Municipal de Oeiras, and nowadays is funded by the German Federal Ministry of Education and Research (BMBF), the West African Science Service Centre on Climate Change and Adapted Land Use (WASCAL) through WASCAL Graduate Studies Programme in Climate Change and Marine Sciences at the Institute for Enginneering and Marine Sciences, Atlantic Technical University, Cabo Verde. The Brazilian agencies that were involved in this project are Conselho Nacional de Desenvolvimento Científico e Tecnológico - CNPq Proc. Nrs 400168/2013-8, and 375781/2013-7 that funded AA, and Fundação de Amparo a Pesquisa no Estado de São Paulo – FAPESP Proc. Nrs 2009/54040-8, 2009/16598-7, and 2008/04050-4 that funded infrastructure to EC. Project FAPESP 2014/07331-5 funded infrastructure to FA. This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – Brasil (CAPES) – Finance Code 1742613 and 88882.317690/2019-01, as a fellowship to CG and Finance Code 001 as a fellowship to TM. AA is now being funded by Fundação para a Ciência e Tecnologia (FCT) of Portugal PTDC/CVT-CVT/28798/2017. Fundação para a Ciência e Tecnologia (FCT) of Portugal provided funds to GHTM (UID/Multi/04413/2020) funded PF, ABA, and SB. Publisher Copyright: Copyright © 2021 Pinto-Almeida, Mendes, Ferreira, Abecasis, Belo, Anibal, Allegretti, Galinaro, Carrilho and Afonso.Schistosomiasis is a chronic neglected tropical disease saddling millions of people in the world, mainly children living in poor rural areas. Praziquantel (PZQ) is currently the only drug used for the treatment and control of this disease. However, the extensive use of this drug has brought concern about the emergence of PZQ-resistance/tolerance by Schistosoma mansoni. Studies of Schistosoma spp. genome, transcriptome, and proteome are crucial to better understand this situation. In this in vitro study, we compare the proteomes of a S. mansoni variant strain stably resistant to PZQ and isogenic to its fully susceptible parental counterpart, identifying proteins from male and female adult parasites of PZQ-resistant and PZQ-susceptible strains, exposed and not exposed to PZQ. A total of 60 Schistosoma spp. proteins were identified, some of which present or absent in either strain, which may putatively be involved in the PZQ-resistance phenomenon. These proteins were present in adult parasites not exposed to PZQ, but some of them disappeared when these adult parasites were exposed to the drug. Understanding the development of PZQ-resistance in S. mansoni is crucial to prolong the efficacy of the current drug and develop markers for monitoring the potential emergence of drug resistance.publishersversionpublishe

HIV-1 gp120 N-linked glycosylation differs between plasma and leukocyte compartments

<p>Abstract</p> <p>Background</p> <p>N-linked glycosylation is a major mechanism for minimizing virus neutralizing antibody response and is present on the Human Immunodeficiency Virus (HIV) envelope glycoprotein. Although it is known that glycosylation changes can dramatically influence virus recognition by the host antibody, the actual contribution of compartmental differences in N-linked glycosylation patterns remains unclear.</p> <p>Methodology and Principal Findings</p> <p>We amplified the <it>env </it>gp120 C2-V5 region and analyzed 305 clones derived from plasma and other compartments from 15 HIV-1 patients. Bioinformatics and Bayesian network analyses were used to examine N-linked glycosylation differences between compartments. We found evidence for cellspecific single amino acid changes particular to monocytes, and significant variation was found in the total number of N-linked glycosylation sites between patients. Further, significant differences in the number of glycosylation sites were observed between plasma and cellular compartments. Bayesian network analyses showed an interdependency between N-linked glycosylation sites found in our study, which may have immense functional relevance.</p> <p>Conclusion</p> <p>Our analyses have identified single cell/compartment-specific amino acid changes and differences in N-linked glycosylation patterns between plasma and diverse blood leukocytes. Bayesian network analyses showed associations inferring alternative glycosylation pathways. We believe that these studies will provide crucial insights into the host immune response and its ability in controlling HIV replication <it>in vivo</it>. These findings could also have relevance in shielding and evasion of HIV-1 from neutralizing antibodies.</p