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Spera AM, Pagliano P, Conti V. Hepatitis C virus eradication in people living with human immunodeficiency virus: Where are we now? World J Hepatol 2024; 16:661-666. [PMID: 38818300 PMCID: PMC11135269 DOI: 10.4254/wjh.v16.i5.661] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2023] [Revised: 03/06/2024] [Accepted: 04/15/2024] [Indexed: 05/22/2024] Open
Abstract
Hepatitis C virus (HCV)/human immunodeficiency virus (HIV) co-infection still involves 2.3 million patients worldwide of the estimated 37.7 million living with HIV, according to World Health Organization. People living with HIV (PLWH) are six times greater affected by HCV, compared to HIV negative ones; the greater prevalence is encountered among people who inject drugs and men who have sex with men: the risk of HCV transmission through sexual contact in this setting can be increased by HIV infection. These patients experience a high rate of chronic hepatitis, which if left untreated progresses to end-stage liver disease and hepatocellular carcinoma (HCC) HIV infection increases the risk of mother to child vertical transmission of HCV. No vaccination against both infections is still available. There is an interplay between HIV and HCV infections. Treatment of HCV is nowadays based on direct acting antivirals (DAAs), HCV treatment plays a key role in limiting the progression of liver disease and reducing the risk of HCC development in mono- and coinfected individuals, especially when used at an early stage of fibrosis, reducing liver disease mortality and morbidity. Since the sustained virological response at week 12 rates were observed in PLWH after HCV eradication, the AASLD has revised its simplified HCV treatment algorithm to also include individuals living with HIV. HCV eradication can determine dyslipidemia, since HCV promotes changes in serum lipid profiles and may influence lipid metabolism. In addition to these apparent detrimental effects on the lipid profile, the efficacy of DAA in HCV/HIV patients needs to be considered in light of its effects on glucose metabolism mediated by improvements in liver function. The aim of the present editorial is to describe the advancement in HCV treatment among PLWH.
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Affiliation(s)
- Anna Maria Spera
- Infectious Disease Unit, Universitary Hospital OORR San Giovanni di Dio e Ruggi d'Aragona, Salerno 84131, Italy.
| | - Pasquale Pagliano
- Department of Infectious Diseases, University of Salerno, Salerno 84131, Italy
| | - Valeria Conti
- Clinical Pharmacology and Pharmacogenetics Unit, University Hospital "San Giovanni di Dio e Ruggi d'Aragona", Salerno 84131, Italy
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CD46 Genetic Variability and HIV-1 Infection Susceptibility. Cells 2021; 10:cells10113094. [PMID: 34831317 PMCID: PMC8622916 DOI: 10.3390/cells10113094] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Accepted: 11/04/2021] [Indexed: 02/07/2023] Open
Abstract
CD46 is the main receptor for complement protein C3 and plays an important role in adaptive immune responses. CD46 genetic variants are associated with susceptibility to several infectious and autoimmune diseases. Additionally, CD46 function can be subverted by HIV-1 to evade attack by complement, a strategy shared by viruses of other families. We sought to determine the association between CD46 gene variants and HIV-1 acquired through intravenous drug use (IDU) and sexual routes (n = 823). Study subjects were of European ancestry and were HIV-1 infected (n = 438) or exposed but seronegative (n = 387). Genotyping of the rs2796265 SNP located in the CD46 gene region was done by allele-specific real-time PCR. A meta-analysis merging IDU and sexual cohorts indicates that the minor genotype (CC) was associated with increased resistance to HIV-1 infection OR = 0.2, 95% CI (0.07–0.61), p = 0.004. The HIV-1-protective genotype is correlated with reduced CD46 expression and alterations in the ratio of CD46 mRNA splicing isoforms.
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Ouladlahsen A, Bensghir R, Baba H, Haddaji A, Abbadi I, Zaidane I, Badi H, Sodqi M, Marih L, Wakrim L, Marhoum El Filali K, Benjelloun S, Ezzikouri S. Lack of Association between IFNL3 Polymorphism and Human Papillomavirus Infection and Their Progression in HIV-Infected Women Receiving Antiretroviral Treatment. Pathobiology 2020; 87:262-267. [PMID: 32428907 DOI: 10.1159/000507763] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2020] [Accepted: 03/18/2020] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND It has been reported that interferon-λ3 (IFNL3)might influence the pathogenesis and clearance of human papillomavirus (HPV) infection. The impact of IFNL3 single-nucleotide polymorphism (SNP) on HPV infection is currently unknown. The aim of this study was to investigate the association between variants in the IFNL3 region and HPV infection in women with human immunodeficiency virus (HIV) infection. METHODS A total of 236 HIV patients, including 65 HPV-negative and 171 HPV DNA-positive women, were enrolled into this study. The IFNL3 rs12979860 polymorphism was genotyped using a predesigned TaqMan SNP genotyping assay. RESULTS Data showed no significant differences in genotypes or allele frequencies between the HPV DNA-positive and the HPV-negative women (p > 0.05). After dividing the HPV-positive women according to cytology results into patients with abnormal and normal lesions, the genotype and allele distribution of the SNP did not significantly differ between the 2 groups (p > 0.05). CONCLUSIONS Our results showed that the IFNL3 rs12979860 polymorphism is not a major determinant of the susceptibility to HPV infection and their progression to abnormal cervical lesions in women living with HIV.
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Affiliation(s)
- Ahd Ouladlahsen
- Service des Maladies Infectieuses, CHU Ibn Rochd, Casablanca, Morocco
| | - Rajaa Bensghir
- Service des Maladies Infectieuses, CHU Ibn Rochd, Casablanca, Morocco
| | - Hanâ Baba
- Virology Unit, Immunovirology Laboratory, Institut Pasteur du Maroc, Casablanca, Morocco
| | - Asmaa Haddaji
- Virology Unit, Viral Hepatitis Laboratory, Institut Pasteur du Maroc, Casablanca, Morocco
| | - Islam Abbadi
- Virology Unit, Viral Hepatitis Laboratory, Institut Pasteur du Maroc, Casablanca, Morocco
| | - Imane Zaidane
- Virology Unit, Viral Hepatitis Laboratory, Institut Pasteur du Maroc, Casablanca, Morocco
| | - Hanan Badi
- Service des Maladies Infectieuses, CHU Ibn Rochd, Casablanca, Morocco
| | - Mustapha Sodqi
- Service des Maladies Infectieuses, CHU Ibn Rochd, Casablanca, Morocco
| | - Latifa Marih
- Service des Maladies Infectieuses, CHU Ibn Rochd, Casablanca, Morocco
| | - Lahcen Wakrim
- Virology Unit, Immunovirology Laboratory, Institut Pasteur du Maroc, Casablanca, Morocco
| | | | - Soumaya Benjelloun
- Virology Unit, Viral Hepatitis Laboratory, Institut Pasteur du Maroc, Casablanca, Morocco
| | - Sayeh Ezzikouri
- Virology Unit, Viral Hepatitis Laboratory, Institut Pasteur du Maroc, Casablanca, Morocco,
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Freitas IT, Tinago W, Sawa H, McAndrews J, Doak B, Prior-Fuller C, Sheehan G, Lambert JS, Muldoon E, Cotter AG, Hall WW, Mallon PWG, Carr MJ. Interferon lambda rs368234815 ΔG/ΔG is associated with higher CD4 +:CD8 + T-cell ratio in treated HIV-1 infection. AIDS Res Ther 2020; 17:13. [PMID: 32295609 PMCID: PMC7194102 DOI: 10.1186/s12981-020-00269-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Accepted: 04/03/2020] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND The objectives of this study were to investigate the relationships between polymorphisms at the interferon lambda (IFNL) locus and CD4+:CD8+ ratio normalisation in people living with HIV (PLWH) on effective antiretroviral therapy (ART); and to examine whether these polymorphisms influence the composition of T lymphocyte compartments in long-term treated HIV-1 infection. METHODS A cross-sectional study in PLWH enrolled into the Mater Immunology study. We performed IFNL genotyping on stored samples and evaluated the association of IFNL single-nucleotide polymorphisms (rs368234815 and rs12979860) with CD4+:CD8+ ratio normalization (> 1) and expanded CD4+ and CD8+ T-cell subsets; CD45RO+CD62L+ (central-memory), CD45RO+ CD62L-(effector-memory) and CD45RO-CD62L+ (naïve), using logistic and linear regression models, respectively. RESULTS 190 ambulatory PLWH recruited to the main study, 143 were included in the analysis (38 had no stored DNA and 9 no T-lymphocyte subpopulation). Of 143 included, the median age (IQR) was 45(39-48) years, 64% were male and 66% were of Caucasian ethnicity. Heterosexual-contact (36%), injecting drug-use (33%) and men who have sex with men (24%) were the most presented HIV-transmission risk groups. The majority of subjects (90.2%) were on ART with 79% of the cohort having an undetectable HIV-RNA (< 40 copies/ml) and the time since ART initiation was 7.5 (3.7-10.4) year. rs368234815 and rs12979860 displayed similar allelic frequencies, with minor alleles ΔG and T representing 39% and 42%, respectively, of circulating alleles. rs368234815 ΔG/ΔG minor homozygotes were significantly associated with increased odds for attaining a normalised CD4+:CD8+ ratio compared to rs368234815 T/T major homozygotes in PLWH virologically suppressed on effective ART (OR = 3.11; 95% CI [1.01:9.56]). rs368234815 ΔG/ΔG homozygosity was also significantly associated with lower levels of CD4+ effector memory T-cells (regression coefficient: - 7.1%, p = 0.04) and CD8+ naïve T-cell subsets were significantly higher in HIV-1 mono-infected PLWH with rs368234815 ΔG/ΔG (regression coefficient: + 7.2%, p = 0.04). CONCLUSIONS In virally-suppressed, long-term ART-treated PLWH, rs368234815 ΔG/ΔG homozygotes were more likely to have attained normalisation of their CD4+:CD8+ ratio, displayed lower CD4+ effector memory and higher naive CD8+ T-cells. Further studies are needed to replicate our findings in other, larger and more diverse cohorts and to determine the impact of IFNL genetic-variation on CD4+:CD8+ ratio normalisation and clinical outcomes in PLWH.
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Affiliation(s)
- Inês T Freitas
- Centre for Experimental Pathogen Host Research, School of Medicine, University College Dublin, Dublin 4, Ireland
| | - Willard Tinago
- Centre for Experimental Pathogen Host Research, School of Medicine, University College Dublin, Dublin 4, Ireland.
| | - Hirofumi Sawa
- Global Station for Zoonosis Control, Global Institution for Collaborative Research and Education (GI-CoRE), Hokkaido University, N20, W10, Kita-ku, Sapporo, 001-0020, Japan
- Global Virus Network (GVN), 801 W. Baltimore St., Baltimore, MD, 21201, USA
| | - Julie McAndrews
- Department of Immunology, Mater Misericordiae University Hospital, Dublin 7, Ireland
| | - Brenda Doak
- Department of Immunology, Mater Misericordiae University Hospital, Dublin 7, Ireland
| | | | - Gerard Sheehan
- Centre for Experimental Pathogen Host Research, School of Medicine, University College Dublin, Dublin 4, Ireland
- Department of Infectious Disease, Mater Misericordiae University Hospital, Dublin 7, Ireland
| | - John S Lambert
- Centre for Experimental Pathogen Host Research, School of Medicine, University College Dublin, Dublin 4, Ireland
- Department of Infectious Disease, Mater Misericordiae University Hospital, Dublin 7, Ireland
| | - Eavan Muldoon
- Department of Infectious Disease, Mater Misericordiae University Hospital, Dublin 7, Ireland
| | - Aoife G Cotter
- Centre for Experimental Pathogen Host Research, School of Medicine, University College Dublin, Dublin 4, Ireland
- Global Virus Network (GVN), 801 W. Baltimore St., Baltimore, MD, 21201, USA
- Department of Infectious Disease, Mater Misericordiae University Hospital, Dublin 7, Ireland
| | - William W Hall
- Centre for Experimental Pathogen Host Research, School of Medicine, University College Dublin, Dublin 4, Ireland
- Global Station for Zoonosis Control, Global Institution for Collaborative Research and Education (GI-CoRE), Hokkaido University, N20, W10, Kita-ku, Sapporo, 001-0020, Japan
- Global Virus Network (GVN), 801 W. Baltimore St., Baltimore, MD, 21201, USA
| | - Patrick W G Mallon
- Centre for Experimental Pathogen Host Research, School of Medicine, University College Dublin, Dublin 4, Ireland
- Department of Infectious Diseases, St Vincent's University Hospital, Dublin 4, Ireland
| | - Michael J Carr
- Global Station for Zoonosis Control, Global Institution for Collaborative Research and Education (GI-CoRE), Hokkaido University, N20, W10, Kita-ku, Sapporo, 001-0020, Japan
- National Virus Reference Laboratory, School of Medicine, University College Dublin, Dublin 4, Ireland
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Fenizia C, Saulle I, Clerici M, Biasin M. Genetic and epigenetic regulation of natural resistance to HIV-1 infection: new approaches to unveil the HESN secret. Expert Rev Clin Immunol 2020; 16:429-445. [PMID: 32085689 DOI: 10.1080/1744666x.2020.1732820] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Introduction: Since the identification of HIV, several studies reported the unusual case of small groups of subjects showing natural resistance to HIV infection. These subjects are referred to as HIV-1-exposed seronegative (HESN) individuals and include people located in different areas, with diverse ethnic backgrounds and routes of exposure. The mechanism/s responsible for protection from infection in HESN individuals are basically indefinite and most likely are multifactorial.Areas covered: Host factors, including genetic background as well as natural and acquired immunity, have all been associated with this phenomenon. Recently, epigenetic factors have been investigated as possible determinants of reduced susceptibility to HIV infection. With the advent of the OMICS era, the availability of techniques such as GWAS, RNAseq, and exome-sequencing in both bulk cell populations and single cells will likely lead to great strides in the understanding of the HESN mystery.Expert opinion: The employment of increasingly sophisticated techniques is allowing the gathering of enormous amounts of data. The integration of such information will provide important hints that could lead to the identification of viral and host correlates of protection against HIV infection, allowing the development of more effective preventative and therapeutic regimens.
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Affiliation(s)
- Claudio Fenizia
- Department of Physiopathology and Transplantation, University of Milan, Milan, Italy
| | - Irma Saulle
- Department of Biomedical and Clinical Sciences "L. Sacco", University of Milan, Milan, Italy
| | - Mario Clerici
- Department of Physiopathology and Transplantation, University of Milan, Milan, Italy.,Don C. Gnocchi Foundation ONLUS, IRCCS, Milan, Italy
| | - Mara Biasin
- Department of Biomedical and Clinical Sciences "L. Sacco", University of Milan, Milan, Italy
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Jaimes-Bernal C, Rallón N, Benito JM, Omar M, Gómez-Vidal MA, Márquez FJ, Sánchez-Arcas B, Trujillo M, Royo JL, Saulle I, Biasin M, Rivero-Juárez A, Caruz A. A Knockout IFNL4 Variant Is Associated With Protection From Sexually Transmitted HIV-1 Infection. J Infect Dis 2019; 219:772-776. [PMID: 30289470 DOI: 10.1093/infdis/jiy584] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2018] [Accepted: 10/04/2018] [Indexed: 11/14/2022] Open
Abstract
An interferon λ4 gene (IFNL4) knockout allele (rs368234815; TT) is associated with spontaneous and IFN-α-dependent cure of hepatitis C virus infection. The role of this polymorphism in the susceptibility to human immunodeficiency virus type 1 (HIV-1) infection is controversial. This study aimed to assess the association of this knockout IFNL4 variant and sexually transmitted HIV-1 infection. A total of 228 HIV-1-positive individuals and 136 HIV-exposed seronegative individuals were investigated for their association with IFNL4 rs368234815 genotypes. The IFNL4 ΔG functional allele is associated with increased susceptibility to HIV-1 infection through the sexual route (odds ratio [OR], 2.1; 95% confidence interval [CI], 1.2-3.6; P = .004). A meta-analysis including a population of injection drug users suggests a codominant mode of inheritance of this risk factor (OR, 2.0; 95% CI, 1.3-3.2; P = .001).
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Affiliation(s)
- Claudia Jaimes-Bernal
- Immunogenetics Unit, Department of Experimental Biology, Universidad de Jaén, Jaen.,Research Group of the Bacteriology and Clinical Laboratory Program, Faculty of Health Sciences, Universidad de Boyacá, Tunja, Colombia
| | - Norma Rallón
- Instituto de Investigación Sanitaria-Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Madrid.,Hospital Universitario Rey Juan Carlos, Móstoles
| | - José M Benito
- Instituto de Investigación Sanitaria-Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Madrid.,Hospital Universitario Rey Juan Carlos, Móstoles
| | - Mohamed Omar
- Infectious Diseases and Clinical Microbiology Unit. Complejo Hospitalario de Jaén, Jaen
| | | | | | | | | | - José Luis Royo
- Department of Surgery, Biochemistry and Immunology, Universidad de Málaga, Málaga
| | - Irma Saulle
- Department of Biomedical and Clinical Sciences "L.-Sacco", University of Milan, Italy
| | - Mara Biasin
- Department of Biomedical and Clinical Sciences "L.-Sacco", University of Milan, Italy
| | - Antonio Rivero-Juárez
- Maimonides Institute for Research in Biomedicine of Cordoba/Hospital Universitario Reina Sofía, Cordoba, Spain
| | - Antonio Caruz
- Immunogenetics Unit, Department of Experimental Biology, Universidad de Jaén, Jaen
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Jõgeda EL, Avi R, Pauskar M, Kallas E, Karki T, Des Jarlais D, Uusküla A, Toompere K, Lutsar I, Huik K. Association of IFNλ4 rs12979860 polymorphism with the acquisition of HCV and HIV infections among people who inject drugs. J Med Virol 2018; 90:1779-1783. [PMID: 29992584 DOI: 10.1002/jmv.25258] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2018] [Accepted: 06/28/2018] [Indexed: 12/24/2022]
Abstract
We investigated the presence of a single-nucleotide polymorphism designated rs12979860 in the interferon λ4 (IFNλ4) gene among 345 people who inject drugs (PWID) and 495 blood donors to evaluate associations between the rs12979860 genotypes and human immunodeficiency virus/hepatitis C virus (HIV/HCV). The rs12979860 TT genotype was over-represented among HIV+ PWID than HIV- PWID and blood donors (16% vs 8% and 10%, P = 0.03, respectively). PWID with TT genotype had approximately twice the probability of being HIV+ (odds ratio [OR], 2.19; 95% confidence interval [CI], 1.11 to 4.33) than PWID without TT. Every additional year of intravenous drug use (IVDU) decreased the OR 1.16 times (OR, 0.86; 95% CI, 0.75 to 0.98). This suggests that rs12979860 TT increases susceptibility to HIV and this impact decreases with increasing duration of IVDU.
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Affiliation(s)
- Ene-Ly Jõgeda
- Department of Microbiology, Institute of Biomedicine and Translational Medicine, Faculty of Medicine, University of Tartu, Tartu, Estonia
| | - Radko Avi
- Department of Microbiology, Institute of Biomedicine and Translational Medicine, Faculty of Medicine, University of Tartu, Tartu, Estonia
| | - Merit Pauskar
- Department of Microbiology, Institute of Biomedicine and Translational Medicine, Faculty of Medicine, University of Tartu, Tartu, Estonia
| | - Eveli Kallas
- Department of Microbiology, Institute of Biomedicine and Translational Medicine, Faculty of Medicine, University of Tartu, Tartu, Estonia
| | - Tõnis Karki
- Department of Microbiology, Institute of Biomedicine and Translational Medicine, Faculty of Medicine, University of Tartu, Tartu, Estonia
| | - Don Des Jarlais
- Department of Environmental Medicine and Public Health, New York, NY, USA
| | - Anneli Uusküla
- Institute of Family Medicine and Public Health, Faculty of Medicine, University of Tartu, Tartu, Estonia
| | - Karolin Toompere
- Institute of Family Medicine and Public Health, Faculty of Medicine, University of Tartu, Tartu, Estonia
| | - Irja Lutsar
- Department of Microbiology, Institute of Biomedicine and Translational Medicine, Faculty of Medicine, University of Tartu, Tartu, Estonia
| | - Kristi Huik
- Department of Microbiology, Institute of Biomedicine and Translational Medicine, Faculty of Medicine, University of Tartu, Tartu, Estonia
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Scagnolari C, Antonelli G. Type I interferon and HIV: Subtle balance between antiviral activity, immunopathogenesis and the microbiome. Cytokine Growth Factor Rev 2018; 40:19-31. [PMID: 29576284 PMCID: PMC7108411 DOI: 10.1016/j.cytogfr.2018.03.003] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2018] [Revised: 02/23/2018] [Accepted: 03/08/2018] [Indexed: 02/06/2023]
Abstract
Type I interferon (IFN) response initially limits HIV-1 spread and may delay disease progression by stimulating several immune system components. Nonetheless, persistent exposure to type I IFN in the chronic phase of HIV-1 infection is associated with desensitization and/or detrimental immune activation, thereby hindering immune recovery and fostering viral persistence. This review provides a basis for understanding the complexity and function of IFN pleiotropic activity in HIV-1 infection. In particular, the dichotomous role of the IFN response in HIV-1 immunopathogenesis will be discussed, highlighting recent advances in the dynamic modulation of IFN production in acute versus chronic infection, expression signatures of IFN subtypes, and viral and host factors affecting the magnitude of IFN response during HIV-1 infection. Lastly, the review gives a forward-looking perspective on the interplay between microbiome compositions and IFN response.
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Affiliation(s)
- Carolina Scagnolari
- Department of Molecular Medicine, Laboratory of Virology Affiliated to Istituto Pasteur Italia - Fondazione Cenci Bolognetti, Sapienza University, Rome, Italy.
| | - Guido Antonelli
- Department of Molecular Medicine, Laboratory of Virology Affiliated to Istituto Pasteur Italia - Fondazione Cenci Bolognetti, Sapienza University, Rome, Italy
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10
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Zaidane I, Wakrim L, Oulad Lahsen A, Bensghir R, Chihab H, Jadid FZ, El Fihry R, Lamdini H, Fayssel N, Marhoum El Filali K, Oudghiri M, Benjelloun S, Ezzikouri S. Interleukin 28B rs12979860 genotype and Human Immunodeficiency Virus type 1: Susceptibility, AIDS development and therapeutic outcome. Hum Immunol 2018; 79:70-75. [PMID: 29080719 DOI: 10.1016/j.humimm.2017.10.011] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2017] [Revised: 08/31/2017] [Accepted: 10/24/2017] [Indexed: 01/02/2023]
Abstract
Human Immunodeficiency Virus type 1 (HIV-1) infection and progression varies widely among individuals. Interferon-λ3 exerts anti-HIV function by activating JAK/STAT pathway-mediated innate immunity. Therefore, we aimed to investigate the association between single nucleotide polymorphisms of the interleukin 28B (IL28B) gene, and the risk of acquisition, AIDS development and therapeutic outcome of HIV-1 in a Moroccan population. A total of 266 HIV-1 seropositive and 158 HIV-1 seronegative subjects were enrolled. Genotyping of rs12979860 of the IL28B was performed using a predesigned TaqMan SNP genotyping assay. No significant association was found between IL28B rs12979860 polymorphism and susceptibility to HIV-1 infection and AIDS development (p > .05). However, in HIV-1 treated patients carrying CC genotype had a more pronounced high levels of CD4+ T-cell compared to subjects with TT genotype (p = .0004). Interestingly, regarding HIV-1 viral load no significant differences between IL28B genotypes in treated and untreated patients were observed (p < .05). IL28B rs12979860 polymorphism not influences the susceptibility to HIV-1 and the AIDS development. However, this polymorphism may affect the response to treatment as measured by CD4+ T cell counts.
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Affiliation(s)
- Imane Zaidane
- Virology Unit, Viral Hepatitis Laboratory, Institut Pasteur du Maroc, Casablanca, Morocco; Virology Unit, Immunovirology Laboratory, Institut Pasteur du Maroc, Casablanca, Morocco
| | - Lahcen Wakrim
- Laboratoire Immunologie et Biodiversité, département de Biologie, Faculté des Sciences Ain Chock, University Hassan II of Casablanca, Casablanca, Morocco
| | - Ahd Oulad Lahsen
- Service des maladies Infectieuses, CHU Ibn Rochd, Casablanca, Morocco
| | - Rajaa Bensghir
- Service des maladies Infectieuses, CHU Ibn Rochd, Casablanca, Morocco
| | - Hajar Chihab
- Virology Unit, Viral Hepatitis Laboratory, Institut Pasteur du Maroc, Casablanca, Morocco
| | - Fatima Zahra Jadid
- Virology Unit, Viral Hepatitis Laboratory, Institut Pasteur du Maroc, Casablanca, Morocco
| | - Raouia El Fihry
- Virology Unit, Viral Hepatitis Laboratory, Institut Pasteur du Maroc, Casablanca, Morocco
| | - Hassan Lamdini
- Service des maladies Infectieuses, CHU Ibn Rochd, Casablanca, Morocco
| | - Naouar Fayssel
- Laboratoire Immunologie et Biodiversité, département de Biologie, Faculté des Sciences Ain Chock, University Hassan II of Casablanca, Casablanca, Morocco
| | | | - Mounia Oudghiri
- Virology Unit, Immunovirology Laboratory, Institut Pasteur du Maroc, Casablanca, Morocco
| | - Soumaya Benjelloun
- Virology Unit, Viral Hepatitis Laboratory, Institut Pasteur du Maroc, Casablanca, Morocco.
| | - Sayeh Ezzikouri
- Virology Unit, Viral Hepatitis Laboratory, Institut Pasteur du Maroc, Casablanca, Morocco.
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Monteleone K, Scheri GC, Statzu M, Selvaggi C, Falasca F, Giustini N, Mezzaroma I, Turriziani O, d'Ettorre G, Antonelli G, Scagnolari C. IFN-stimulated gene expression is independent of the IFNL4 genotype in chronic HIV-1 infection. Arch Virol 2016; 161:3263-8. [PMID: 27558125 DOI: 10.1007/s00705-016-3016-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2016] [Accepted: 08/12/2016] [Indexed: 01/16/2023]
Abstract
This study aimed to evaluate the association between the IFNL4 rs368234815 (ΔG/TT) dinucleotide polymorphism and the IFN response during chronic HIV-1 infection. We carried out genotyping analysis and measured the expression of IFN-stimulated genes (ISGs) (myxovirus resistance protein A [MxA], ISG15, ISG56, apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like [APOBEC] 3F and APOBEC3G) on peripheral blood mononuclear cells collected from naïve and HAART-treated HIV-1-infected patients. There were no statistically significant differences in endogenous ISGs mRNA levels among HIV-1-positive patients bearing different IFNL4 genotypes, suggesting that ISG expression is independent of the IFNL4 genotype in HIV-1 infection.
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Affiliation(s)
- Katia Monteleone
- Laboratory of Virology, Department of Molecular Medicine, Istituto Pasteur Italia-Cenci Bolognetti Fondazione, Sapienza University of Rome, Viale di Porta Tiburtina n° 28, 00185, Rome, Italy
| | - Giuseppe Corano Scheri
- Laboratory of Virology, Department of Molecular Medicine, Istituto Pasteur Italia-Cenci Bolognetti Fondazione, Sapienza University of Rome, Viale di Porta Tiburtina n° 28, 00185, Rome, Italy
| | - Maura Statzu
- Laboratory of Virology, Department of Molecular Medicine, Istituto Pasteur Italia-Cenci Bolognetti Fondazione, Sapienza University of Rome, Viale di Porta Tiburtina n° 28, 00185, Rome, Italy
| | - Carla Selvaggi
- Laboratory of Virology, Department of Molecular Medicine, Istituto Pasteur Italia-Cenci Bolognetti Fondazione, Sapienza University of Rome, Viale di Porta Tiburtina n° 28, 00185, Rome, Italy
| | - Francesca Falasca
- Laboratory of Virology, Department of Molecular Medicine, Istituto Pasteur Italia-Cenci Bolognetti Fondazione, Sapienza University of Rome, Viale di Porta Tiburtina n° 28, 00185, Rome, Italy
| | - Noemi Giustini
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, Rome, Italy
| | - Ivano Mezzaroma
- Department of Clinical Medicine, Sapienza University of Rome, Rome, Italy
| | - Ombretta Turriziani
- Laboratory of Virology, Department of Molecular Medicine, Istituto Pasteur Italia-Cenci Bolognetti Fondazione, Sapienza University of Rome, Viale di Porta Tiburtina n° 28, 00185, Rome, Italy
| | - Gabriella d'Ettorre
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, Rome, Italy
| | - Guido Antonelli
- Laboratory of Virology, Department of Molecular Medicine, Istituto Pasteur Italia-Cenci Bolognetti Fondazione, Sapienza University of Rome, Viale di Porta Tiburtina n° 28, 00185, Rome, Italy
| | - Carolina Scagnolari
- Laboratory of Virology, Department of Molecular Medicine, Istituto Pasteur Italia-Cenci Bolognetti Fondazione, Sapienza University of Rome, Viale di Porta Tiburtina n° 28, 00185, Rome, Italy.
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12
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Chinnaswamy S. Gene-disease association with human IFNL locus polymorphisms extends beyond hepatitis C virus infections. Genes Immun 2016; 17:265-75. [PMID: 27278127 PMCID: PMC7091887 DOI: 10.1038/gene.2016.24] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2016] [Revised: 04/01/2016] [Accepted: 05/06/2016] [Indexed: 12/25/2022]
Abstract
Interferon (IFN) lambda (IFN-λ or type III IFN) gene polymorphisms were discovered in the year 2009 to have a strong association with spontaneous and treatment-induced clearance of hepatitis C virus (HCV) infection in human hosts. This landmark discovery also brought renewed interest in type III IFN biology. After more than half a decade since this discovery, we now have reports that show that genetic association of IFNL gene polymorphisms in humans is not limited only to HCV infections but extends beyond, to include varied diseases such as non-alcoholic fatty liver disease, allergy and several other viral diseases including that caused by the human immunodeficiency virus. Notably, all these conditions have strong involvement of host innate immune responses. After the discovery of a deletion polymorphism that leads to the expression of a functional IFN-λ4 as the prime 'functional' variant, the relevance of other polymorphisms regulating the expression of IFN-λ3 is in doubt. Herein, I seek to critically address these issues and review the current literature to provide a framework to help further understanding of IFN-λ biology.
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Affiliation(s)
- S Chinnaswamy
- National Institute of Biomedical Genomics, Kalyani, West Bengal India
- Department of Clinical Immunology, Rheumatology and Allergy, Healthy Ageing Research Centre, Medical University of Lodz, Lodz, Poland
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13
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HIV-1 Promoter Single Nucleotide Polymorphisms Are Associated with Clinical Disease Severity. PLoS One 2016; 11:e0150835. [PMID: 27100290 PMCID: PMC4839606 DOI: 10.1371/journal.pone.0150835] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2015] [Accepted: 02/20/2016] [Indexed: 12/13/2022] Open
Abstract
The large majority of human immunodeficiency virus type 1 (HIV-1) markers of disease progression/severity previously identified have been associated with alterations in host genetic and immune responses, with few studies focused on viral genetic markers correlate with changes in disease severity. This study presents a cross-sectional/longitudinal study of HIV-1 single nucleotide polymorphisms (SNPs) contained within the viral promoter or long terminal repeat (LTR) in patients within the Drexel Medicine CNS AIDS Research and Eradication Study (CARES) Cohort. HIV-1 LTR SNPs were found to associate with the classical clinical disease parameters CD4+ T-cell count and log viral load. They were found in both defined and undefined transcription factor binding sites of the LTR. A novel SNP identified at position 108 in a known COUP (chicken ovalbumin upstream promoter)/AP1 transcription factor binding site was significantly correlated with binding phenotypes that are potentially the underlying cause of the associated clinical outcome (increase in viral load and decrease in CD4+ T-cell count).
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14
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Abstract
The interferon (IFN)L4 polymorphism rs368234815 is associated with hepatitis C virus (HCV) spontaneous clearance and response to IFN-based treatments. The role of this polymorphism in HIV-1 infection is controversial. We investigated whether genetic variation at IFNL4 is associated to HIV-1 acquisition. The HCV protective allele TT was associated with decreased likelihood of HIV-1 infection in male intravenous drug users [odds ratio (OR): 0.3; P = 0.006], and this association was not modified by the genotype of CCR5. These results suggest that genetic susceptibility to HCV and HIV-1 infection shares common molecular pathways.
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15
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Piluso A, Giannini C, Fognani E, Gragnani L, Caini P, Monti M, Petrarca A, Ranieri J, Urraro T, Triboli E, Laffi G, Zignego AL. Value of IL28B genotyping in patients with HCV-related mixed cryoglobulinemia: results of a large, prospective study. J Viral Hepat 2013; 20:e107-14. [PMID: 23490377 DOI: 10.1111/jvh.12017] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2012] [Accepted: 09/03/2012] [Indexed: 12/19/2022]
Abstract
HCV-related mixed cryoglobulinemia (MC) is characterized by clonal expansion of B cells producing a polyreactive natural antibody (rheumatoid factor) and interferon (IFN)-based therapy is the first therapeutic option in mild-moderate MC. Single nucleotide polymorphisms (SNPs) proximal to genes involved in the innate response (IL28B/IFN-λ gene family) are strongly associated with spontaneous and IFN-induced viral clearance in hepatitis C, but no data exist about their role in HCV-positive MC. A large cohort of patients with HCV and MC was studied to evaluate the influence of IL28B genotype on the response to treatment and/or the evolution to MC of HCV infection. The rs12979860/rs8099917 IL28B polymorphisms were analysed in 481 consecutive HCV-positive subjects (250 with MC and 231 without MC, as controls) using real-time PCR and direct sequencing. Hundred and fifteen HCV patients with MC received standard anti-HCV therapy, and the results were evaluated according to the IL28B SNP distribution. Similar IL28B SNPs allele frequencies were recorded for patients and controls. IL28B major allele homozygosis (for both SNPs tested) was tightly correlated with virological and clinical response (P = 0.002). A statistically significant association was limited to 'difficult-to-treat' (G1/4) HCV genotypes. The IL28B genotype was a strong independent predictor of response (P = 0.007, OR 6.06; CI 1.65-22.22). The IL28B genotype was confirmed to be a useful predictor of response to IFN-based therapy in patients with HCV and MC. The very close correlation between IL28B SNP distribution, virological and clinical response definitively confirmed the key role played by HCV in MC. Conversely, the IL28B genotype does not seem to influence the evolution to MC.
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Affiliation(s)
- A Piluso
- Center for Systemic Manifestations of Hepatitis Viruses (MaSVE), Department of Internal Medicine, University of Florence, Florence, Italy
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16
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Machmach K, Abad-Molina C, Romero-Sánchez MC, Abad MA, Ferrando-Martínez S, Genebat M, Pulido I, Viciana P, González-Escribano MF, Leal M, Ruiz-Mateos E. IL28B single-nucleotide polymorphism rs12979860 is associated with spontaneous HIV control in white subjects. J Infect Dis 2013; 207:651-5. [PMID: 23225905 DOI: 10.1093/infdis/jis717] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2023] Open
Abstract
The single-nucleotide polymorphism (SNP) rs12979860 near the IL28B gene has been associated with the spontaneous clearance of hepatitis C virus. We sought to determine whether this SNP could be associated with the spontaneous control of human immunodeficiency virus (HIV) infection. We studied the prevalence of the IL28B CC genotype among 53 white HIV controllers, compared with the prevalence among 389 HIV-infected noncontrollers. We found that the IL28B CC genotype was independently associated with spontaneous HIV control (odds ratio [OR], 2.669; P = .017), as were female sex (OR, 7.077; P ≤ .001) and the presence of HLA-B57 and/or B27 (OR, 3.080; P = .017). This result supports the idea that common host mechanisms are involved in the spontaneous control of these 2 chronic infections.
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Affiliation(s)
- Kawthar Machmach
- Laboratory of Immunovirology, Biomedicine Institute of Seville, Clinic Unit of Infectious Diseases, Microbiology and Preventive Medicine, Seville, Spain
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17
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Sanabani SS, Nukui Y, Pereira J, da Costa AC, de Oliveira ACS, Pessôa R, Leal FE, Segurado AC, Kallas EG, Sabino EC. Lack of evidence to support the association of a single IL28B genotype SNP rs12979860 with the HTLV-1 clinical outcomes and proviral load. BMC Infect Dis 2012; 12:374. [PMID: 23259930 PMCID: PMC3547796 DOI: 10.1186/1471-2334-12-374] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2012] [Accepted: 12/20/2012] [Indexed: 01/25/2023] Open
Abstract
BACKGROUND The Interleukin 28B (IL28B) rs12979860 polymorphisms was recently reported to be associated with the human T-cell leukemia virus type 1 (HTLV-1) proviral load (PvL) and the development of the HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). METHODS In an attempt to examine this hypothesis, we assessed the association of the rs12979860 genotypes with HTLV-1 PvL levels and clinical status in 112 unrelated Brazilian subjects (81 HTLV-1 asymptomatic carriers, 24 individuals with HAM/TSP and 7 with Adult T cell Leukemia/Lymphoma (ATLL)). RESULTS All 112 samples were successfully genotyped and their PvLs compared. Neither the homozygote TT nor the heterozygote CT mutations nor the combination genotypes (TT/CT) were associated with a greater PvL. We also observed no significant difference in allele distribution between asymptomatic carriers and patients with HTLV-1 associated HAM/TSP. CONCLUSIONS Our study failed to support the previously reported positive association between the IL28B rs12979860 polymorphisms and an increased risk of developing HAM/TSP in the Brazilian population.
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Affiliation(s)
- Sabri Saeed Sanabani
- Clinical Laboratory, Department of Pathology, LIM 03, Hospital das Clínicas (HC), School of Medicine, University of São Paulo, São Paulo, Brazil
- São Paulo Inistitute of Tropical Medicine, São Paulo, Brazil
| | - Youko Nukui
- Department of Hematology, University of São Paulo, São Paulo, Brazil
| | - Juliana Pereira
- Department of Hematology, University of São Paulo, São Paulo, Brazil
| | - Antonio Charlys da Costa
- Clinical Laboratory, Department of Pathology, LIM 03, Hospital das Clínicas (HC), School of Medicine, University of São Paulo, São Paulo, Brazil
| | - Ana Carolina Soares de Oliveira
- Clinical Laboratory, Department of Pathology, LIM 03, Hospital das Clínicas (HC), School of Medicine, University of São Paulo, São Paulo, Brazil
| | - Rodrigo Pessôa
- Clinical Laboratory, Department of Pathology, LIM 03, Hospital das Clínicas (HC), School of Medicine, University of São Paulo, São Paulo, Brazil
| | - Fabio Eudes Leal
- Division of Clinical Immunology and Allergy, University of Sao Paulo Medical School, São Paulo, Brazil
| | - Aluisio C Segurado
- Deparment of Infectious Diseases, School of Medicine, University of Sao Paulo, São Paulo, Brazil
| | - Esper Georges Kallas
- Division of Clinical Immunology and Allergy, University of Sao Paulo Medical School, São Paulo, Brazil
| | - Ester Cerdeira Sabino
- Deparment of Infectious Diseases, School of Medicine, University of Sao Paulo, São Paulo, Brazil
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18
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Parczewski M, Bander D, Leszczyszyn-Pynka M, Urbańska A, Socha Ł, Boroń-Kaczmarska A. IL28B CC genotype is associated with higher all-cause mortality in antiretroviral-treated HIV-infected patients. AIDS Res Hum Retroviruses 2012; 28:1640-6. [PMID: 22545770 DOI: 10.1089/aid.2011.0354] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Il28B single nucleotide polymorphisms were found to influence interferon λ expression, resulting in changes in hepatitis C virus (HCV)-RNA serum levels as well as the HIV-RNA set point prior to combined antiretroviral therapy (cART). To date, there is limited information on the influence of this polymorphism on survival in HIV-infected, treatment-naïve, and antiretroviral-treated patients. Longitudinal data from 484 patients diagnosed with HIV infection (including 406 on cART) were analyzed to investigate the association between Il28B rs 1979860 variants and all-cause mortality. Kaplan-Meyer and Cox models were used to calculate the hazard ratio associated with IL28B genotypes predictive of a greater likelihood of survival for patients prior to the introduction of cART and for patients on cART. The IL28B genotype frequencies were 41.7% (n=202) for CC, 46.5% (n=225) for CT, and 11.7% (n=57) for TT patients. The CC variant was associated with higher mortality (46 cases, 22.8%) compared to other genotypes [n=31 (13.8%) and n=7 (12.3%) for CT and TT, respectively, p=0.02]. IL28 genotypes did not influence the survival probability prior to treatment initiation (HR 1.04, 95% CI: 0.84-1.24, p=0.68). In antiretroviral-treated patients, after adjustment for gender, baseline CD4 count, CDC category at HIV diagnosis, and age (multivariate HR 1.75, 95% CI: 1.20-2.30, p=0.047), the CC genotype was associated with a decreased probability of survival when compared to the non-CC genotype (univariate HR 1.8, 95% CI: 1.28-2.34, p=0.029). IL28B rs12979860 genotypes influence mortality risk in HIV-infected, antiretroviral-treated patients. The effect may be related to higher baseline plasma HIV viremia and possibly altered immune reconstitution associated with interferon λ expression.
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Affiliation(s)
- Miłosz Parczewski
- Department of Infectious Diseases and Hepatology, Pomeranian Medical University, Szczecin, Poland.
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19
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Scagnolari C, Midulla F, Riva E, Monteleone K, Solimini A, Bonci E, Cangiano G, Papoff P, Moretti C, Pierangeli A, Antonelli G. Evaluation of interleukin 28B single nucleotide polymorphisms in infants suffering from bronchiolitis. Virus Res 2012; 165:236-40. [PMID: 22374338 PMCID: PMC7114428 DOI: 10.1016/j.virusres.2012.02.018] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2011] [Revised: 02/14/2012] [Accepted: 02/16/2012] [Indexed: 12/15/2022]
Abstract
The genetic diversity of the host is believed to be the key of the diversity in the clinical presentation of bronchiolitis. The aim of this study was to determine whether the known rs12979860 and rs8099917 single nucleotide polymorphisms (SNPs) in interleukin (IL)28B region, influence clinical features and natural history of bronchiolitis. Both SNPs showed no significant association with the risk of hospitalization for respiratory syncytial virus (RSV), viral load, disease severity, and other clinical features of patients. Interestingly infants carrying IL28B rs12979860 TT genotype had lower age at hospital admission than that of infants carrying CC/CT genotypes. Overall our results indicate that both IL28B SNPs had no impact on the clinical course of bronchiolitis with the only exception of the IL28B rs12979860 SNP which increased the risk of hospitalization for bronchiolitis at early age.
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Affiliation(s)
- Carolina Scagnolari
- Department of Molecular Medicine, Laboratory of Virology, "Sapienza" University of Rome, Italy.
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20
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Molina Pérez E, Fernández Castroagudín J, Domínguez Muñoz E. [Current indications for triple therapy in hepatitis C virus infection]. GASTROENTEROLOGIA Y HEPATOLOGIA 2012; 35:266-77. [PMID: 22410706 DOI: 10.1016/j.gastrohep.2012.01.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/10/2012] [Accepted: 01/19/2012] [Indexed: 10/28/2022]
Abstract
Chronic hepatitis C virus (HCV) infection is the main cause of liver cirrhosis and liver carcinoma in western countries. There is evidence that HCV clearance induced by antiviral therapy is beneficial, increasing survival and reducing the complications of cirrhosis. Triple therapy with boceprevir or telaprevir associated with pegylated interferon and ribavirin has increased rates of sustained viral response both in treatment-naïve patients and in those failing previous regimens. Before treating patients with these new molecules, physicians should be familiar with their indications and the regimens to be used. Furthermore, both adverse events and the development of resistances must be monitored. The main aims are careful selection of patients and of the regimen to be used, and achieving adequate adherence to obtain optimal results.
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Affiliation(s)
- Esther Molina Pérez
- Unidad de Hepatología, Servicio de Aparato Digestivo, Hospital Clínico Universitario de Santiago, Santiago de Compostela, España
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21
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Younossi ZM, Birerdinc A, Estep M, Stepanova M, Afendy A, Baranova A. The impact of IL28B genotype on the gene expression profile of patients with chronic hepatitis C treated with pegylated interferon alpha and ribavirin. J Transl Med 2012; 10:25. [PMID: 22313623 PMCID: PMC3296607 DOI: 10.1186/1479-5876-10-25] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2011] [Accepted: 02/07/2012] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Recent studies of CH-C patients have demonstrated a strong association between IL28B CC genotype and sustained virologic response (SVR) after PEG-IFN/RBV treatment. We aimed to assess whether IL28B alleles rs12979860 genotype influences gene expression in response to PEG-IFN/RBV in CH-C patients. METHODS Clinical data and gene expression data were available for 56 patients treated with PEG-IFN/RBV. Whole blood was used to determine IL28B genotypes. Differential expression of 153 human genes was assessed for each treatment time point (Days: 0, 1, 7, 28, 56) and was correlated with IL28B genotype (IL28B C/C or non-C/C) over the course of the PEG-IFN/RBV treatment. Genes with statistically significant changes in their expression at each time point were used as an input for pathway analysis using KEGG Pathway Painter (KPP). Pathways were ranked based on number of gene involved separately per each study cohort. RESULTS The most striking difference between the response patterns of patients with IL28B C/C and T* genotypes during treatment, across all pathways, is a sustained pattern of treatment-induced gene expression in patients carrying IL28B C/C. In the case of IL28B T* genotype, pre-activation of genes, the lack of sustained pattern of gene expression or a combination of both were observed. This observation could potentially provide an explanation for the lower rate of SVR observed in these patients. Additionally, when the lists of IL28B genotype-specific genes which were differentially expressed in patients without SVR were compared at their baseline, IRF2 and SOCS1 genes were down-regulated regardless of patients' IL28B genotype. Furthermore, our data suggest that CH-C patients who do not have the SOCS1 gene silenced have a better chance of achieving SVR. Our observations suggest that the action of SOCS1 is independent of IL28B genotype. CONCLUSIONS IL28B CC genotype patients with CH-C show a sustained treatment-induced gene expression profile which is not seen in non-CC genotype patients. Silencing of SOCS1 is a negative and independent predictor of SVR. These data may provide some mechanistic explanation for higher rate of SVR in IL28B CC patients who are treated with PEG-IFN/RBV.
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Affiliation(s)
- Zobair M Younossi
- Betty and Guy Beatty Center for Integrated Research, Inova Health System, Falls Church, VA, USA
- Center for the Study of Genomics in Liver Diseases, School of Systems Biology, College of Science, George Mason University, Fairfax, VA, USA
- Center for Liver Diseases and Department of Medicine, Inova Fairfax Hospital, Falls Church, VA, USA
| | - Aybike Birerdinc
- Betty and Guy Beatty Center for Integrated Research, Inova Health System, Falls Church, VA, USA
- Center for the Study of Genomics in Liver Diseases, School of Systems Biology, College of Science, George Mason University, Fairfax, VA, USA
| | - Mike Estep
- Betty and Guy Beatty Center for Integrated Research, Inova Health System, Falls Church, VA, USA
- Center for Liver Diseases and Department of Medicine, Inova Fairfax Hospital, Falls Church, VA, USA
| | - Maria Stepanova
- Betty and Guy Beatty Center for Integrated Research, Inova Health System, Falls Church, VA, USA
- Center for the Study of Genomics in Liver Diseases, School of Systems Biology, College of Science, George Mason University, Fairfax, VA, USA
- Center for Liver Diseases and Department of Medicine, Inova Fairfax Hospital, Falls Church, VA, USA
| | - Arian Afendy
- Betty and Guy Beatty Center for Integrated Research, Inova Health System, Falls Church, VA, USA
- Center for Liver Diseases and Department of Medicine, Inova Fairfax Hospital, Falls Church, VA, USA
| | - Ancha Baranova
- Betty and Guy Beatty Center for Integrated Research, Inova Health System, Falls Church, VA, USA
- Center for the Study of Genomics in Liver Diseases, School of Systems Biology, College of Science, George Mason University, Fairfax, VA, USA
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22
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Lunge VR, da Rocha DB, Béria JU, Tietzmann DC, Stein AT, Simon D. IL28B polymorphism associated with spontaneous clearance of hepatitis C infection in a Southern Brazilian HIV type 1 population. AIDS Res Hum Retroviruses 2012; 28:215-9. [PMID: 21790472 DOI: 10.1089/aid.2011.0096] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
About one-third of people infected with human immunodeficiency virus-1 (HIV-1) are coinfected with hepatitis C virus (HCV) because of shared transmission routes. Studies report that HIV-1 complicates hepatitis C infection by increasing HCV viral load and reducing spontaneous clearance. Single nucleotide polymorphisms (SNPs) upstream of the IL28B gene have been associated with spontaneous and treatment-induced clearance of HCV infection. The aim of this study was to evaluate the association between the SNP rs12979860 of the IL28B gene and spontaneous clearance of HCV infection in a Brazilian HIV-1 population. The SNP was analyzed by polymerase chain reaction (PCR) followed by restriction digestion in 138 anti-HCV-positive patients. Spontaneous clearance was observed in 34 subjects (24.6%). Genotype distribution was significantly different between spontaneous clearance and HCV chronic patients. The CT/TT genotypes conferred a nearly 3-fold increased odds to chronic HCV infection relative to the CC genotype (odds ratio, 2.78; 95% confidence interval, 1.16-6.64; p=0.011). In conclusion, the rs12979860 polymorphism is associated with spontaneous clearance of HCV in HIV-1 Brazilian infected patients.
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Affiliation(s)
- Vagner Ricardo Lunge
- Programa de Pós-Graduação em Diagnóstico Genético e Molecular, Universidade Luterana do Brasil, Canoas, RS, Brazil
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Abstract
The introduction of direct acting antiviral agents (DAAs) will markedly change treatment options for individuals who have a chronic HCV infection. Within the next few months, licensing of two HCV protease inhibitors (boceprevir and telaprevir) for the treatment of patients with chronic hepatitis C as part of a triple therapy with PEG-IFN-α and ribavirin is anticipated in the USA, Europe and many other countries. Final results of pivotal phase III clinical trials in previously untreated and treatment-experienced patients with HCV genotype 1 infection were presented at the Annual Meeting of the American Association for the Study of the Liver 2010 held in Boston, MA, USA, and at the Annual Conference of the Asian Pacific Association for the Study of the Liver 2011, held in Bangkok, Thailand. This article summarizes the results of these phase III trials in consideration of accumulating data on important baseline and on-treatment predictive factors for treatment response, such as the host IL28B genotype and the rapid virologic response; the introduction of these new therapies into clinical practice is also covered. Furthermore, preliminary data on the combination of different classes of DAAs, such as HCV protease inhibitors and HCV polymerase inhibitors, without interferon α are discussed.
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Affiliation(s)
- Wolf Peter Hofmann
- Medizinische Klinik 1, Klinikum der Johann Wolfgang Goethe-Universität, Theodor Stern-Kai 7, Frankfurt am Main 60590, Germany
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