Origin and Epidemiological History of HIV-1 CRF14_BG

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Users must also make clear the license terms under which the work was published. CC BY Licence: http://creativecommons.org/licenses/by/4.0/Background: CRF14_BG isolates, originally found in Spain, are characterized by CXCR4 tropism and rapid disease progression. This study aimed to identify the origin of CRF14_BG and reconstruct its epidemiological history based on new isolates from Portugal.Methodology/Principal Findings: C2V3C3 env gene sequences were obtained from 62 samples collected in 1993–1998 from Portuguese HIV-1 patients. Full-length genomic sequences were obtained from three patients. Viral subtypes, diversity, divergence rate and positive selection were investigated by phylogenetic analysis. The molecular structure of the genomes was determined by bootscanning. A relaxed molecular clock model was used to date the origin of CRF14_BG. Geno2pheno was used to predict viral tropism. Subtype B was the most prevalent subtype (45 sequences; 73%) followed by CRF14_BG (8; 13%), G (4; 6%), F1 (2; 3%), C (2; 3%) and CRF02_AG (1; 2%). Three CRF14_BG sequences were derived from 1993 samples. Near full-length genomic sequences were strongly related to the CRF14_BG isolates from Spain. Genetic diversity of the Portuguese isolates was significantly higher than the Spanish isolates (0.044 vs 0.014, P,0.0001). The mean date of origin of the CRF14_BG cluster was estimated to be 1992 (range, 1989 and 1996) based on the subtype G genomic region and 1989 (range, 1984–1993) based on the subtype B genomic region. Most CRF14_BG strains (78.9%) were predicted to be CXCR4. Finally, up to five amino acids were under selective pressure in subtype B V3 loop whereas only one was found in the CRF14_BG cluster.Conclusions: CRF14_BG emerged in Portugal in the early 1990 s soon after the beginning of the HIV-1 epidemics, spread to Spain in late 1990 s as a consequence of IVDUs migration and then to the rest of Europe. CXCR4 tropism is a general characteristic of this CRF that may have been selected for by escape from neutralizing antibody response

Hundreds of variants clustered in genomic loci and biological pathways affect human height

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.

Whole-genome sequence-based analysis of thyroid function

Tiina Paunio on työryhmän UK10K Consortium jäsen.Normal thyroid function is essential for health, but its genetic architecture remains poorly understood. Here, for the heritable thyroid traits thyrotropin (TSH) and free thyroxine (FT4), we analyse whole-genome sequence data from the UK10K project (N = 2,287). Using additional whole-genome sequence and deeply imputed data sets, we report meta-analysis results for common variants (MAF >= 1%) associated with TSH and FT4 (N = 16,335). For TSH, we identify a novel variant in SYN2 (MAF = 23.5%, P = 6.15 x 10(-9)) and a new independent variant in PDE8B (MAF = 10.4%, P = 5.94 x 10(-14)). For FT4, we report a low-frequency variant near B4GALT6/ SLC25A52 (MAF = 3.2%, P = 1.27 x 10(-9)) tagging a rare TTR variant (MAF = 0.4%, P = 2.14 x 10(-11)). All common variants explain >= 20% of the variance in TSH and FT4. Analysis of rare variants (MAFPeer reviewe

The Impact of Genetic Diversity on HIV-1 Molecular Epidemiology and Antiviral Drug Resistance

HIV-1 is a retrovirus that jumped from chimpanzees and/or gorillas to hu mans in the first half of the twentieth century. After its transmission to humans, it acquired a high amount of genetic diversity, due to high r ates of mutation and recombination. Until now, nine subtypes (A, B, C, D , F, G H, J and K) and 43 Circulating Recombinant Forms (CRFs) have been described. Furthermore, several Unique Recombinant Forms (URFs) are con tinuously generated when different subtypes recombine. To understand the impact of HIV-1 genetic diversity on its molecular epidemiology, evolut ionary dynamics and response to antiretrovirals, we used bioinformatics methods combining phylogenetic analysis, population genetics, statistica l and data mining approaches. Understanding the molecular epidemiology of HIV-1 and its changes along time is crucial to better monitor the pandemic and to develop efficient vaccines and antiretrovirals. In Chapter 2 of this thesis, we describe t he molecular epidemiology of HIV-1 in Angola, a country geographically c lose to Democratic Republic of Congo (DRC), currently known as the origi n of the pandemic. In our sample of Angolan patients, we found an enormo us amount of genetic diversity, including a high number of recombinant f orms, only comparable to its neighboring country DRC. In Chapter 3, we d escribe the molecular epidemiology of HIV-1 in Europe in patients newly diagnosed in 2002-2003. We found a large amount of non-B subtypes (33%), which seem to be mainly infecting immigrants, heterosexuals and women. Our studies indicate that non-B subtypes seem still to be restrained to certain risk groups and to patients originated from continents other tha n Europe, suggesting their continuous import in Europe. The origin and evolutionary history of HIV-1 subtypes is still a largely debated issue. In Chapter 4, we studied the origin of subtype G and CRF 02_AG and found that subtype G is in fact a recombinant, which may be at least partly originating from CRF02_AG, thus inversing the role of par ent and recombinant . Our study brings new striking data, especially b ecause until now the origin of HIV-1 subtypes was thought to be due to f ounder and sampling effects. Our new data indicates that recombination o ccurred already early on in the epidemic and is affecting also the so-ca lled pure subtypes. In Chapter 5, we analyze the evolutionary rate of different subtypes and CRFs. Our results suggest that the evolutionary rate is subtype-depende nt and that it can be attributed not only to host immune pressure measur ed in the nonsynonymous substitution rate, but also to the replicative f itness of the subtypes/CRFs measured in the synonymous substitution rate . Our results suggest that the different HIV-1 subtypes or CRFs have ind eed different biological properties, some of which may explain the diffe rences in the epidemics of these subtypes/CRFs. In the last part of this thesis we evaluate the effect of all these epid emic and genetic differences on HIV-1 antiretroviral therapy. This issue has been widely studied in the last few years. However, in this thesis we develop new approaches for the study of therapy response. We consider each subtype as an individual and compare each subtype to its own wild- type, unlike previous studies, which have considered subtype B as the gl obal wild-type of all subtypes. In Chapter 6, we investigate the baselin e susceptibility of subtypes C, F, G and CRF02_AG to protease inhibitors . We found differences in baseline susceptibility of different subtypes that become more evident if we group our sequences according to certain polymorphisms in protease instead of grouping it by subtypes, suggesting it is the actual genetic background that makes the difference, and not some other characteristic of the subtypes. In Chapter 7, we analyze the effect on therapy response of 89I/V mutations, which is different among the different subtypes. We find that the mutation is indeed associated w ith PI treatment, but only in several non-B subtypes, including subtype G, that have 89M as wild-type sequence, as opposed to 89L as wild-type i n other subtypes. Its phenotypic effect is only measurable when combined with the L90M mutation. These mutations are further studied in Chapter 8 in the context of the comparison of the interpretation of genotypic an d phenotypic data of subtypes B and G. Interestingly, the combination of M89I/L90M in subtype G has a phenotypic effect on susceptibility to nel finavir comparable to the L90M only as major mutation in subtype B. This argues that failing nelfinavir results in similar phenotypic effects in subtype B compared to subtype G, but for this effect, 2 mutations are n eeded in subtype G, while only one mutation is needed in subtype B. In conclusion, the epidemics of HIV-1 and the genetic differences among the resulting subtypes and CRFs result in different biological propertie s and play a role in resistance development towards antiviral treatment. This raises questions on how such differences should be implemented in drug resistance interpretation systems that have traditionally been buil t on information from subtype B.status: publishe

Relatório estágio profissional

Relatório final do estágio profissionalizante do 6.º ano

Determinants of Late HIV Presentation at Ndlavela Health Center in Mozambique

Funding Information: Funding: This research was partially supported by the Camões, I.P., Portuguese Foundation for Science and Technology through the projects GHTM-UID/04413/2020 and MARVEL (PTDC/SAU-PUB/4018/2021) and by the Gilead Génese program (HIVLatePresenters project). Funding Information: This research was partially supported by the Cam?es, I.P., Portuguese Foundation for Science and Technology through the projects GHTM-UID/04413/2020 and MARVEL (PTDC/SAU-PUB/4018/2021) and by the Gilead G?nese program (HIVLatePresenters project). Publisher Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland.Background: There has been tremendous progress in the fight against HIV worldwide; however, challenges persist in the control of HIV infection. These challenges include the high prevalence of late presenters. There are many disadvantages of late presentation—from reduced survival of the infected person to the risk of transmitting the infection. This research aims to analyze the factors that influence the late presentation in patients attending Ndlavela Health Center in Mozambique. Methodology: A retrospective cross-sectional study was carried out at Ndlavela Health Center including patients diagnosed with HIV between 2015 and 2020. The European Late Presenter Consensus working group definitions were used, and univariate and multivariate logistic regression were used to identify factors associated with late presentation. Results: In total, 519 participants were included in the study, of which nearly 47% were classified as late presenters. The male gender (AOR = 2.41), clinical suspicious test (AOR = 4.03), initiated by the health professional (AOR = 2.1,9), and fear of stigma (AOR = 2.80) were the main risk factors for late HIV presentation. Conclusion: Factors that are potentially determinant for late HIV presentation were identified. Actions are needed to focus on risk factors that are most likely to delay presentation.publishersversionpublishe

Effect of human immunodeficiency virus type 1 protease inhibitor therapy and subtype on development of resistance in subtypes B and G

Europe is currently observing a significant rise in non-B subtypes. Consequently, the effect of genetic variability on therapy response or genotypic resistance interpretation algorithms is an emerging concern. The purpose of this study is to investigate the amino acid substitutions selected under drug pressure in the protease of human immunodeficiency virus type 1 (HIV-1) subtypes B and G, and determine if there are any significant differences. We investigated therapy-related and subtype-related substitutions in the protease, considering subtype, overall protease inhibitor treatment and individual drug exposure. Many mutations were significantly related to protease inhibitor (PI) therapy, with mutations exclusive to subtype B or subtype G. Some mutations are at positions related to resistance in both subtypes, but the amino acid substitution is different. Other mutations were significantly associated with subtype and PI selective pressure (p<0.05), pointing towards a differential selective pressure in both subtypes. We confirmed previous reports on the subtype-dependent selection of D30N and 89I, and identified a new mutation with such differential selective pressure: 37D was preferentially selected by lopinavir in subtype B. Other novel mutations found under therapy pressure were 13A, 35N, K55R, I66F, I72L/T, T74S, 82M and 89I/V. Our study indicates that even though in general, drug selective pressure and resistance pathways are relatively similar between subtypes B and G, some differences do occur, leading to subtype-dependent substitutions.status: publishe

Origin and epidemiological history of HIV-1 CRF14_BG

Background CRF14_BG isolates, originally found in Spain, are characterized by CXCR4 tropism and rapid disease progression. This study aimed to identify the origin of CRF14_BG and reconstruct its epidemiological history based on new isolates from Portugal. Methodology/Principal Findings C2V3C3 env gene sequences were obtained from 62 samples collected in 1993–1998 from Portuguese HIV-1 patients. Full-length genomic sequences were obtained from three patients. Viral subtypes, diversity, divergence rate and positive selection were investigated by phylogenetic analysis. The molecular structure of the genomes was determined by bootscanning. A relaxed molecular clock model was used to date the origin of CRF14_BG. Geno2pheno was used to predict viral tropism. Subtype B was the most prevalent subtype (45 sequences; 73%) followed by CRF14_BG (8; 13%), G (4; 6%), F1 (2; 3%), C (2; 3%) and CRF02_AG (1; 2%). Three CRF14_BG sequences were derived from 1993 samples. Near full-length genomic sequences were strongly related to the CRF14_BG isolates from Spain. Genetic diversity of the Portuguese isolates was significantly higher than the Spanish isolates (0.044 vs 0.014, P<0.0001). The mean date of origin of the CRF14_BG cluster was estimated to be 1992 (range, 1989 and 1996) based on the subtype G genomic region and 1989 (range, 1984–1993) based on the subtype B genomic region. Most CRF14_BG strains (78.9%) were predicted to be CXCR4. Finally, up to five amino acids were under selective pressure in subtype B V3 loop whereas only one was found in the CRF14_BG cluster. Conclusions CRF14_BG emerged in Portugal in the early 1990 s soon after the beginning of the HIV-1 epidemics, spread to Spain in late 1990 s as a consequence of IVDUs migration and then to the rest of Europe. CXCR4 tropism is a general characteristic of this CRF that may have been selected for by escape from neutralizing antibody response.This work was supported by grant PTDC/SAU-FCF/67673/2006 from Fundação para a Ciência e Tecnologia Portugal, and by CHAIN (Collaborative HIV and Anti-HIV Drug Resistance Network), European Union. Inês Bártolo and Pedro Borrego are recipients of PhD scholarships from Fundação para a Ciência e Tecnologia (FCT), Portugal. Ana Abecasis is supported by a Post-Doc grant from the Fundação para a Ciência e Tecnologia (FCT), Portugal (SFRH/BPD/65605/2009). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.info:eu-repo/semantics/publishedVersio

Protease mutation M89I/V is linked to therapy failure in patients infected with the HIV-1 non-B subtypes C, F or G

OBJECTIVE: To investigate whether and how mutations at position 89 of HIV-1 protease were associated with protease inhibitor (PI) failure, and what is the impact of the HIV-1 subtype. METHODS: In a database containing pol nucleotide sequences and treatment history, the correlation between PI experience and mutations at codon 89 was determined separately for subtype B and several non-B subtypes. A Bayesian network model was used to map the resistance pathways in which M89I/V is involved for subtype G. The phenotypic effect of M89I/V for several PIs was also measured. RESULTS: The analysis showed that for the subtypes C, F and G in which the wild-type codon at 89 was M compared to L for subtype B, M89I/V was significantly more frequently observed in PI-treated patients displaying major resistance mutations to PIs than in drug-naive patients. M89I/V was strongly associated with PI resistance mutations at codons 71, 74 and 90. Phenotypically, M89I/V alone did not confer a reduced susceptibility to PIs. However, when combined with L90M, a significantly reduced susceptibility to nelfinavir was observed (P < 0.05) in comparison with strains with L90M alone. CONCLUSIONS: The results of the present study show that M89I/V is associated with PI experience in subtypes C, F and G but not in subtype B. M89I/V should be considered a secondary PI mutation with an important effect on nelfinavir susceptibility in the presence of L90M.status: publishe