Transposable elements may enhance antiviral resistance in HIV-1 elite controllers
Abstract Background Less than 0.5% of people living with HIV-1 are elite controllers (ECs)—individuals who maintain undetectable plasma viremia without antiretroviral therapy, despite having replication-competent viral reservoirs. While EC CD4+ T cells have been investigated for gene expression sign...
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BMC
2025-02-01
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| Series: | Genome Biology |
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| Online Access: | https://doi.org/10.1186/s13059-025-03484-y |
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| author | Manvendra Singh Sabrina M. Leddy Luis Pedro Iñiguez Matthew L. Bendall Douglas F. Nixon Cédric Feschotte |
| author_facet | Manvendra Singh Sabrina M. Leddy Luis Pedro Iñiguez Matthew L. Bendall Douglas F. Nixon Cédric Feschotte |
| author_sort | Manvendra Singh |
| collection | DOAJ |
| description | Abstract Background Less than 0.5% of people living with HIV-1 are elite controllers (ECs)—individuals who maintain undetectable plasma viremia without antiretroviral therapy, despite having replication-competent viral reservoirs. While EC CD4+ T cells have been investigated for gene expression signatures associated with HIV-1 resistance, the expression and regulatory activity of transposable elements (TEs) remain unexplored. TEs can directly impact host immune responses to pathogens, including HIV-1, suggesting their activities could contribute to HIV-1 elite control. To begin testing this hypothesis, we conduct a TE-centric analysis of public multi-omics data from ECs and other populations. Results We find the CD4+ T cell transcriptome and retrotranscriptome of ECs are distinct from healthy controls, from people living with HIV-1 on antiretroviral therapy, and from viremic progressors. However, there is substantial transcriptomic heterogeneity among ECs. We categorize ECs into four clusters with distinct expression and chromatin accessibility profiles of TEs and antiviral factors. Several TE families with known immuno-regulatory activity are differentially expressed among ECs. Their expression positively correlates with their chromatin accessibility in ECs and negatively correlates with the expression of their KRAB zinc-finger (KZNF) repressors. This coordinated, locus-level variation forms a network of putative cis-regulatory elements for genes involved in HIV-1 restriction. Conclusions We propose that the EC phenotype is driven in part by reduced KZNF-mediated repression of specific TE-derived cis-regulatory elements for antiviral genes, heightening their resistance against HIV-1. Our study reveals heterogeneity in the EC CD4+ T cell transcriptome, including variable expression of TEs and their KZNF controllers, that must be considered when deciphering HIV-1 control mechanisms. |
| format | Article |
| id | doaj-art-4652d1ca25fd4b56bd2d915a2f64159b |
| institution | DOAJ |
| issn | 1474-760X |
| language | English |
| publishDate | 2025-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Genome Biology |
| spelling | doaj-art-4652d1ca25fd4b56bd2d915a2f64159b2025-08-20T03:04:34ZengBMCGenome Biology1474-760X2025-02-0126112910.1186/s13059-025-03484-yTransposable elements may enhance antiviral resistance in HIV-1 elite controllersManvendra Singh0Sabrina M. Leddy1Luis Pedro Iñiguez2Matthew L. Bendall3Douglas F. Nixon4Cédric Feschotte5Department of Molecular Biology and Genetics, Cornell UniversityDepartment of Molecular Biology and Genetics, Cornell UniversityCentre for Genomic Regulation (CRG), The Barcelona Institute of Science and TechnologyDivision of Infectious Diseases, Department of Medicine, Weill Cornell MedicineDivision of Infectious Diseases, Department of Medicine, Weill Cornell MedicineDepartment of Molecular Biology and Genetics, Cornell UniversityAbstract Background Less than 0.5% of people living with HIV-1 are elite controllers (ECs)—individuals who maintain undetectable plasma viremia without antiretroviral therapy, despite having replication-competent viral reservoirs. While EC CD4+ T cells have been investigated for gene expression signatures associated with HIV-1 resistance, the expression and regulatory activity of transposable elements (TEs) remain unexplored. TEs can directly impact host immune responses to pathogens, including HIV-1, suggesting their activities could contribute to HIV-1 elite control. To begin testing this hypothesis, we conduct a TE-centric analysis of public multi-omics data from ECs and other populations. Results We find the CD4+ T cell transcriptome and retrotranscriptome of ECs are distinct from healthy controls, from people living with HIV-1 on antiretroviral therapy, and from viremic progressors. However, there is substantial transcriptomic heterogeneity among ECs. We categorize ECs into four clusters with distinct expression and chromatin accessibility profiles of TEs and antiviral factors. Several TE families with known immuno-regulatory activity are differentially expressed among ECs. Their expression positively correlates with their chromatin accessibility in ECs and negatively correlates with the expression of their KRAB zinc-finger (KZNF) repressors. This coordinated, locus-level variation forms a network of putative cis-regulatory elements for genes involved in HIV-1 restriction. Conclusions We propose that the EC phenotype is driven in part by reduced KZNF-mediated repression of specific TE-derived cis-regulatory elements for antiviral genes, heightening their resistance against HIV-1. Our study reveals heterogeneity in the EC CD4+ T cell transcriptome, including variable expression of TEs and their KZNF controllers, that must be considered when deciphering HIV-1 control mechanisms.https://doi.org/10.1186/s13059-025-03484-yGenomicsHIVRetrovirusesImmunologyGene regulationTransposable elements |
| spellingShingle | Manvendra Singh Sabrina M. Leddy Luis Pedro Iñiguez Matthew L. Bendall Douglas F. Nixon Cédric Feschotte Transposable elements may enhance antiviral resistance in HIV-1 elite controllers Genome Biology Genomics HIV Retroviruses Immunology Gene regulation Transposable elements |
| title | Transposable elements may enhance antiviral resistance in HIV-1 elite controllers |
| title_full | Transposable elements may enhance antiviral resistance in HIV-1 elite controllers |
| title_fullStr | Transposable elements may enhance antiviral resistance in HIV-1 elite controllers |
| title_full_unstemmed | Transposable elements may enhance antiviral resistance in HIV-1 elite controllers |
| title_short | Transposable elements may enhance antiviral resistance in HIV-1 elite controllers |
| title_sort | transposable elements may enhance antiviral resistance in hiv 1 elite controllers |
| topic | Genomics HIV Retroviruses Immunology Gene regulation Transposable elements |
| url | https://doi.org/10.1186/s13059-025-03484-y |
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