0000000000199952
AUTHOR
Enrique Ortega
Genetic Variability of Hepatitis C Virus before and after Combined Therapy of Interferon plus Ribavirin
We present an analysis of the selective forces acting on two hepatitis C virus genome regions previously postulated to be involved in the viral response to combined antiviral therapy. One includes the three hypervariable regions in the envelope E2 glycoprotein, and the other encompasses the PKR binding domain and the V3 domain in the NS5A region. We used a cohort of 22 non-responder patients to combined therapy (interferon alpha-2a plus ribavirin) for which samples were obtained before initiation of therapy and after 6 or/and 12 months of treatment. A range of 25-100 clones per patient, genome region and time sample were sequenced. These were used to detect general patterns of adaptation, t…
Genetic variability in hepatitis C virus and its role in antiviral treatment response
Summary. Hepatitis C virus (HCV) is a major health problem worldwide, infecting an estimated 170 million people. The high genetic variability of HCV contributes to the chronicity of hepatitis C. Here, we report results from a large-scale sequence analysis of 67 patients infected with HCV genotype 1, 23 with subtype 1a and 44 with subtype 1b. Two regions of the HCV genome were analysed in samples prior to combined therapy with alpha interferon plus ribavirin, one compressing the hypervariable regions (HVR1, HVR2 and HVR3) of the E2 glycoprotein and another one including the interferon-sensitive determining region (ISDR) and the V3 domain of the NS5A protein. Genetic diversity measures showe…
Combined Therapy of Interferon Plus Ribavirin Promotes Multiple Adaptive Solutions in Hepatitis C Virus
Hepatitis C virus (HCV) presents several regions involved potentially in evading antiviral treatment and host immune system. Two regions, known as PKR-BD and V3 domains, have been proposed to be involved in resistance to interferon. Additionally, hypervariable regions in the envelope E2 glycoprotein are also good candidates to participate in evasion from the immune system. In this study, we have used a cohort of 22 non-responder patients to combined therapy (interferon alpha-2a plus ribavirin) for which samples obtained just before initiation of therapy and after 6 or/and 12 months of treatment were available. A range of 25-100 clones per patient, genome region and time sample were obtained…
Identification of a large, fast-expanding HIV-1 subtype B transmission cluster among MSM in Valencia, Spain
We describe and characterize an exceptionally large HIV-1 subtype B transmission cluster occurring in the Comunidad Valenciana (CV, Spain). A total of 1806 HIV-1 protease-reverse transcriptase (PR/RT) sequences from different patients were obtained in the CV between 2004 and 2014. After subtyping and generating a phylogenetic tree with additional HIV-1 subtype B sequences, a very large transmission cluster which included almost exclusively sequences from the CV was detected (n = 143 patients). This cluster was then validated and characterized with further maximum-likelihood phylogenetic analyses and Bayesian coalescent reconstructions. With these analyses, the CV cluster was delimited to 11…
A new subtype of hepatitis C virus genotype 1: complete genome and phylogenetic relationships of an Equatorial Guinea isolate.
Hepatitis C virus (HCV) is the leading cause of chronic liver disease and is associated with hepatocellular carcinoma. However, there have been few studies on the distribution and genetic diversity of HCV isolates in non-developed countries. Here, the complete genome sequence of an HCV genotype 1 isolate from Equatorial Guinea is reported, the first complete HCV-1 genome of African origin. Phylogenetic analysis revealed that this sequence always grouped with sequences of genotype 1, but did not group clearly with any subtype described so far. An analysis of partial NS5B gene sequences with additional sequences of African origin also failed to find close similarities between the new sequenc…
Refined analysis of genetic variability parameters in hepatitis C virus and the ability to predict antiviral treatment response.
Summary. Hepatitis C virus (HCV) infects approximately 3% of the world population. The chronicity of hepatitis C seems to depend on the level of genetic variability. We have recently (Torres-Puente et al., J Viral Hepat, 2008; 15: 188) reported genetic variability estimates from a large-scale sequence analysis of 67 patients infected with HCV subtypes 1a (23 patients) and 1b (44 patients) and related them to response, or lack of, to alpha-interferon plus ribavirin treatment.. Two HCV genome regions were analysed in samples prior to antiviral therapy, one compressing the three hypervariable regions of the E2 glycoprotein and another one including the interferon sensitive determining region …
Evidence of Recombination in Intrapatient Populations of Hepatitis C Virus.
Hepatitis C virus (HCV) is a major cause of liver disease worldwide and a potential cause of substantial morbidity and mortality in the future. HCV is characterized by a high level of genetic heterogeneity. Although homologous recombination has been demonstrated in many members of the family Flaviviridae, to which HCV belongs, there are only a few studies reporting recombination on natural populations of HCV, suggesting that these events are rare in vivo. Furthermore, these few studies have focused on recombination between different HCV genotypes/subtypes but there are no reports on the extent of intra-genotype or intra-subtype recombination between viral strains infecting the same patient.…
Effect of antiviral treatment and host susceptibility on positive selection in hepatitis C virus (HCV).
Abstract We have conducted a large sequence study of the E1–E2 and NS5A regions of the HCV, subtypes 1a and b, both in patients previously treated with interferon, and untreated patients, who later responded, or not, to a combination therapy based on interferon plus ribavirin. We have examined the role played by the number of positively selected sites on disease progression and its relationship with several variables such as patients’ age, sex and their risk of acquiring the disease. We have detected three groups of patients that respond or not to combination therapy: responders of intermediate age, older non-responders and young non-responders, they possess an increasing average number of …
Epidemic dynamics of two coexisting hepatitis C virus subtypes.
Hepatitis C virus (HCV) infection affects about 3 % of the human population. Phylogenetic analyses have grouped its variants into six major genotypes, which have a star-like distribution and several minor subtypes. The most abundant genotype in Europe is the so-called genotype 1, with two prevalent subtypes, 1a and 1b. In order to explain the higher prevalence of subtype 1b over 1a, a large-scale sequence analysis (100 virus clones) has been carried out over 25 patients of both subtypes in two regions of the HCV genome: one comprising hypervariable region 1 and another including the interferon sensitivity-determining region. Neither polymorphism analysis nor molecular variance analysis (att…
Hepatitis C virus and the controversial role of the interferon sensitivity determining region in the response to interferon treatment
The degree of variability of the interferon sensitivity determining region (ISDR) in the hepatitis C virus (HCV) genome has been postulated to predict the response to interferon therapy, mainly in patients infected with subtype 1b, although this prediction has been the subject of a long controversy. This prediction has been tested by analyzing a cohort of 67 Spanish patients infected with HCV genotype 1, 23 of which were infected with subtype 1a and 44 with subtype 1b. A sample previous to therapy with α-interferon plus ribavirin was obtained and several clones (between 25 and 96) including the ISDR were sequenced from each patient. A significant correlation between mutations at the ISDR an…
Expansion of the CRF19_cpx Variant in Spain
Abstract Background HIV-1 CRF19_cpx, is a recombinant variant found almost exclusively in Cuba and recently associated to a faster AIDS onset. Infection with this variant leads to higher viral loads and levels of RANTES and CXCR4 co-receptor use. Objectives The goal of this study was to assess the presence of CRF19_cpx in the Spanish province of Valencia, given its high pathogenicity. Study design 1294 HIV-1 protease-reverse transcriptase (PR/RT) sequences were obtained in Valencia (Spain), between 2005 and 2014. After subtyping, the detected CRF19_cpx sequences were aligned with 201 CRF19_cpx and 66 subtype D sequences retrieved from LANL, and subjected to maximum-likelihood phylogenetic a…
Contribution of insertions and deletions to the variability of hepatitis C virus populations
Little is known about the potential effects of insertions and deletions (indels) on the evolutionary dynamics of hepatitis C virus (HCV). In fact, the consequences of indels on antiviral treatment response are a field of investigation completely unexplored. Here, an extensive sequencing project was undertaken by cloning and sequencing serum samples from 25 patients infected with HCV subtype 1a and 48 patients with subtype 1b. For 23 patients, samples obtained after treatment with alpha interferon plus ribavirin were also available. Two genome fragments containing the hypervariable regions in the envelope 2 glycoprotein and the PKR-BD domain in NS5A were sequenced, yielding almost 16 000 seq…
Using evolutionary tools to refine the new hypervariable region 3 within the envelope 2 protein of hepatitis C virus
Abstract The envelope 2 protein of hepatitis C virus (HCV) presents three hypervariable regions, named HVR1, HVR2 and HVR3, in which the presence of antigenic sites has been described. Genetic variability in these regions may reflect the generation of escape mutants as a consequence of the immune response. Therefore, these regions would tend to accumulate amino acid changes along the infection process, an effect that could be accelerated by antiviral treatments. In this study, we have analyzed the E1–E2 region of 23 HCV patients non-responders to antiviral treatment, 7 of which were infected with subtype 1a, 15 with subtype 1b, and 1 with a new HCV-1 subtype, before and after 6 and/or 12 mo…
The molecular epidemiology of HIV-1 in the Comunidad Valenciana (Spain): analysis of transmission clusters
AbstractHIV infections are still a very serious concern for public heath worldwide. We have applied molecular evolution methods to study the HIV-1 epidemics in the Comunidad Valenciana (CV, Spain) from a public health surveillance perspective. For this, we analysed 1804 HIV-1 sequences comprising protease and reverse transcriptase (PR/RT) coding regions, sampled between 2004 and 2014. These sequences were subtyped and subjected to phylogenetic analyses in order to detect transmission clusters. In addition, univariate and multinomial comparisons were performed to detect epidemiological differences between HIV-1 subtypes, and risk groups. The HIV epidemic in the CV is dominated by subtype B i…
Organoplatinum(II) Complexes Self-Assemble and Recognize AT-Rich Duplex DNA Sequences
The specific recognition of AT-rich DNA sequences opens up the door to promising diagnostic and/or therapeutic strategies against gene-related diseases. Here, we demonstrate that amphiphilic PtII complexes of the type [Pt(dmba)(N∧N)]NO3 (dmba = N,N-dimethylbenzylamine-κN, κC; N∧N = dpq (3), dppz (4), and dppn (5)) recognize AT-rich oligonucleotides over other types of DNA, RNA, and model proteins. The crystal structure of 4 shows the presence of significant π-stacking interactions and a distorted coordination sphere of the d8 PtII atom. Complex 5, containing the largest π-conjugated ligand, forms supramolecular assemblies at high concentrations under aqueous environment. However, its aggreg…
CCDC 1998467: Experimental Crystal Structure Determination
Related Article: Ana Zamora, Erin Wachter, María Vera, David K. Heidary, Venancio Rodríguez, Enrique Ortega, Vanesa Fernández-Espín, Christoph Janiak, Edith C. Glazer, Giampaolo Barone, José Ruiz|2021|Inorg.Chem.|60|2178|doi:10.1021/acs.inorgchem.0c02648
CCDC 1515373: Experimental Crystal Structure Determination
Related Article: Ana Zamora, Erin Wachter, María Vera, David K. Heidary, Venancio Rodríguez, Enrique Ortega, Vanesa Fernández-Espín, Christoph Janiak, Edith C. Glazer, Giampaolo Barone, José Ruiz|2021|Inorg.Chem.|60|2178|doi:10.1021/acs.inorgchem.0c02648