Methylation regulation of Antiviral host factors, Interferon Stimulated Genes (ISGs) and T-cell responses associated with natural HIV control.
GWAS, immune analyses and biomarker screenings have identified host factors associated with in vivo HIV-1 control. However, there is a gap in the knowledge about the mechanisms that regulate the expression of such host factors. Here, we aimed to assess DNA methylation impact on host genome in natura...
| Main Authors: | , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2020-08-01
|
| Series: | PLoS Pathogens |
| Online Access: | https://doi.org/10.1371/journal.ppat.1008678 |
| _version_ | 1818716712908881920 |
|---|---|
| author | Bruna Oriol-Tordera Maria Berdasco Anuska Llano Beatriz Mothe Cristina Gálvez Javier Martinez-Picado Jorge Carrillo Julià Blanco Clara Duran-Castells Carmela Ganoza Jorge Sanchez Bonaventura Clotet Maria Luz Calle Alex Sánchez-Pla Manel Esteller Christian Brander Marta Ruiz-Riol |
| author_facet | Bruna Oriol-Tordera Maria Berdasco Anuska Llano Beatriz Mothe Cristina Gálvez Javier Martinez-Picado Jorge Carrillo Julià Blanco Clara Duran-Castells Carmela Ganoza Jorge Sanchez Bonaventura Clotet Maria Luz Calle Alex Sánchez-Pla Manel Esteller Christian Brander Marta Ruiz-Riol |
| author_sort | Bruna Oriol-Tordera |
| collection | DOAJ |
| description | GWAS, immune analyses and biomarker screenings have identified host factors associated with in vivo HIV-1 control. However, there is a gap in the knowledge about the mechanisms that regulate the expression of such host factors. Here, we aimed to assess DNA methylation impact on host genome in natural HIV-1 control. To this end, whole DNA methylome in 70 untreated HIV-1 infected individuals with either high (>50,000 HIV-1-RNA copies/ml, n = 29) or low (<10,000 HIV-1-RNA copies/ml, n = 41) plasma viral load (pVL) levels were compared and identified 2,649 differentially methylated positions (DMPs). Of these, a classification random forest model selected 55 DMPs that correlated with virologic (pVL and proviral levels) and HIV-1 specific adaptive immunity parameters (IFNg-T cell responses and neutralizing antibodies capacity). Then, cluster and functional analyses identified two DMP clusters: cluster 1 contained hypo-methylated genes involved in antiviral and interferon response (e.g. PARP9, MX1, and USP18) in individuals with high viral loads while in cluster 2, genes related to T follicular helper cell (Tfh) commitment (e.g. CXCR5 and TCF7) were hyper-methylated in the same group of individuals with uncontrolled infection. For selected genes, mRNA levels negatively correlated with DNA methylation, confirming an epigenetic regulation of gene expression. Further, these gene expression signatures were also confirmed in early and chronic stages of infection, including untreated, cART treated and elite controllers HIV-1 infected individuals (n = 37). These data provide the first evidence that host genes critically involved in immune control of the virus are under methylation regulation in HIV-1 infection. These insights may offer new opportunities to identify novel mechanisms of in vivo virus control and may prove crucial for the development of future therapeutic interventions aimed at HIV-1 cure. |
| first_indexed | 2024-12-17T19:23:37Z |
| format | Article |
| id | doaj.art-932994bc041b404db54d93aecb303cb6 |
| institution | Directory Open Access Journal |
| issn | 1553-7366 1553-7374 |
| language | English |
| last_indexed | 2024-12-17T19:23:37Z |
| publishDate | 2020-08-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj.art-932994bc041b404db54d93aecb303cb62022-12-21T21:35:27ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742020-08-01168e100867810.1371/journal.ppat.1008678Methylation regulation of Antiviral host factors, Interferon Stimulated Genes (ISGs) and T-cell responses associated with natural HIV control.Bruna Oriol-TorderaMaria BerdascoAnuska LlanoBeatriz MotheCristina GálvezJavier Martinez-PicadoJorge CarrilloJulià BlancoClara Duran-CastellsCarmela GanozaJorge SanchezBonaventura ClotetMaria Luz CalleAlex Sánchez-PlaManel EstellerChristian BranderMarta Ruiz-RiolGWAS, immune analyses and biomarker screenings have identified host factors associated with in vivo HIV-1 control. However, there is a gap in the knowledge about the mechanisms that regulate the expression of such host factors. Here, we aimed to assess DNA methylation impact on host genome in natural HIV-1 control. To this end, whole DNA methylome in 70 untreated HIV-1 infected individuals with either high (>50,000 HIV-1-RNA copies/ml, n = 29) or low (<10,000 HIV-1-RNA copies/ml, n = 41) plasma viral load (pVL) levels were compared and identified 2,649 differentially methylated positions (DMPs). Of these, a classification random forest model selected 55 DMPs that correlated with virologic (pVL and proviral levels) and HIV-1 specific adaptive immunity parameters (IFNg-T cell responses and neutralizing antibodies capacity). Then, cluster and functional analyses identified two DMP clusters: cluster 1 contained hypo-methylated genes involved in antiviral and interferon response (e.g. PARP9, MX1, and USP18) in individuals with high viral loads while in cluster 2, genes related to T follicular helper cell (Tfh) commitment (e.g. CXCR5 and TCF7) were hyper-methylated in the same group of individuals with uncontrolled infection. For selected genes, mRNA levels negatively correlated with DNA methylation, confirming an epigenetic regulation of gene expression. Further, these gene expression signatures were also confirmed in early and chronic stages of infection, including untreated, cART treated and elite controllers HIV-1 infected individuals (n = 37). These data provide the first evidence that host genes critically involved in immune control of the virus are under methylation regulation in HIV-1 infection. These insights may offer new opportunities to identify novel mechanisms of in vivo virus control and may prove crucial for the development of future therapeutic interventions aimed at HIV-1 cure.https://doi.org/10.1371/journal.ppat.1008678 |
| spellingShingle | Bruna Oriol-Tordera Maria Berdasco Anuska Llano Beatriz Mothe Cristina Gálvez Javier Martinez-Picado Jorge Carrillo Julià Blanco Clara Duran-Castells Carmela Ganoza Jorge Sanchez Bonaventura Clotet Maria Luz Calle Alex Sánchez-Pla Manel Esteller Christian Brander Marta Ruiz-Riol Methylation regulation of Antiviral host factors, Interferon Stimulated Genes (ISGs) and T-cell responses associated with natural HIV control. PLoS Pathogens |
| title | Methylation regulation of Antiviral host factors, Interferon Stimulated Genes (ISGs) and T-cell responses associated with natural HIV control. |
| title_full | Methylation regulation of Antiviral host factors, Interferon Stimulated Genes (ISGs) and T-cell responses associated with natural HIV control. |
| title_fullStr | Methylation regulation of Antiviral host factors, Interferon Stimulated Genes (ISGs) and T-cell responses associated with natural HIV control. |
| title_full_unstemmed | Methylation regulation of Antiviral host factors, Interferon Stimulated Genes (ISGs) and T-cell responses associated with natural HIV control. |
| title_short | Methylation regulation of Antiviral host factors, Interferon Stimulated Genes (ISGs) and T-cell responses associated with natural HIV control. |
| title_sort | methylation regulation of antiviral host factors interferon stimulated genes isgs and t cell responses associated with natural hiv control |
| url | https://doi.org/10.1371/journal.ppat.1008678 |
| work_keys_str_mv | AT brunaorioltordera methylationregulationofantiviralhostfactorsinterferonstimulatedgenesisgsandtcellresponsesassociatedwithnaturalhivcontrol AT mariaberdasco methylationregulationofantiviralhostfactorsinterferonstimulatedgenesisgsandtcellresponsesassociatedwithnaturalhivcontrol AT anuskallano methylationregulationofantiviralhostfactorsinterferonstimulatedgenesisgsandtcellresponsesassociatedwithnaturalhivcontrol AT beatrizmothe methylationregulationofantiviralhostfactorsinterferonstimulatedgenesisgsandtcellresponsesassociatedwithnaturalhivcontrol AT cristinagalvez methylationregulationofantiviralhostfactorsinterferonstimulatedgenesisgsandtcellresponsesassociatedwithnaturalhivcontrol AT javiermartinezpicado methylationregulationofantiviralhostfactorsinterferonstimulatedgenesisgsandtcellresponsesassociatedwithnaturalhivcontrol AT jorgecarrillo methylationregulationofantiviralhostfactorsinterferonstimulatedgenesisgsandtcellresponsesassociatedwithnaturalhivcontrol AT juliablanco methylationregulationofantiviralhostfactorsinterferonstimulatedgenesisgsandtcellresponsesassociatedwithnaturalhivcontrol AT claradurancastells methylationregulationofantiviralhostfactorsinterferonstimulatedgenesisgsandtcellresponsesassociatedwithnaturalhivcontrol AT carmelaganoza methylationregulationofantiviralhostfactorsinterferonstimulatedgenesisgsandtcellresponsesassociatedwithnaturalhivcontrol AT jorgesanchez methylationregulationofantiviralhostfactorsinterferonstimulatedgenesisgsandtcellresponsesassociatedwithnaturalhivcontrol AT bonaventuraclotet methylationregulationofantiviralhostfactorsinterferonstimulatedgenesisgsandtcellresponsesassociatedwithnaturalhivcontrol AT marialuzcalle methylationregulationofantiviralhostfactorsinterferonstimulatedgenesisgsandtcellresponsesassociatedwithnaturalhivcontrol AT alexsanchezpla methylationregulationofantiviralhostfactorsinterferonstimulatedgenesisgsandtcellresponsesassociatedwithnaturalhivcontrol AT manelesteller methylationregulationofantiviralhostfactorsinterferonstimulatedgenesisgsandtcellresponsesassociatedwithnaturalhivcontrol AT christianbrander methylationregulationofantiviralhostfactorsinterferonstimulatedgenesisgsandtcellresponsesassociatedwithnaturalhivcontrol AT martaruizriol methylationregulationofantiviralhostfactorsinterferonstimulatedgenesisgsandtcellresponsesassociatedwithnaturalhivcontrol |