Efficient mRNA delivery to resting T cells to reverse HIV latency
Abstract A major hurdle to curing HIV is the persistence of integrated proviruses in resting CD4+ T cells that remain in a transcriptionally silent, latent state. One strategy to eradicate latent HIV is to activate viral transcription, followed by elimination of infected cells through virus-mediated...
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Nature Portfolio
2025-05-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-60001-2 |
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| author | Paula M. Cevaal Stanislav Kan Bridget M. Fisher Michael A. Moso Abigail Tan Haiyin Liu Abdalla Ali Kiho Tanaka Rory A. Shepherd Youry Kim Jesslyn Ong Denzil L. Furtado Marvin Holz Damian F. J. Purcell Joshua M. L. Casan Thomas Payne Wei Zhao Mohamed Fareh James H. McMahon Steven G. Deeks Rebecca Hoh Sushama Telwatte Colin W. Pouton Angus P. R. Johnston Frank Caruso Jori Symons Sharon R. Lewin Michael Roche |
| author_facet | Paula M. Cevaal Stanislav Kan Bridget M. Fisher Michael A. Moso Abigail Tan Haiyin Liu Abdalla Ali Kiho Tanaka Rory A. Shepherd Youry Kim Jesslyn Ong Denzil L. Furtado Marvin Holz Damian F. J. Purcell Joshua M. L. Casan Thomas Payne Wei Zhao Mohamed Fareh James H. McMahon Steven G. Deeks Rebecca Hoh Sushama Telwatte Colin W. Pouton Angus P. R. Johnston Frank Caruso Jori Symons Sharon R. Lewin Michael Roche |
| author_sort | Paula M. Cevaal |
| collection | DOAJ |
| description | Abstract A major hurdle to curing HIV is the persistence of integrated proviruses in resting CD4+ T cells that remain in a transcriptionally silent, latent state. One strategy to eradicate latent HIV is to activate viral transcription, followed by elimination of infected cells through virus-mediated cytotoxicity or immune-mediated clearance. We hypothesised that mRNA-lipid nanoparticle (LNP) technology would provide an opportunity to deliver mRNA encoding proteins able to reverse HIV latency in resting CD4+ T cells. Here we develop an LNP formulation (LNP X) with unprecedented potency to deliver mRNA to hard-to-transfect resting CD4+ T cells in the absence of cellular toxicity or activation. Encapsulating an mRNA encoding the HIV Tat protein, an activator of HIV transcription, LNP X enhances HIV transcription in ex vivo CD4+ T cells from people living with HIV. LNP X further enables the delivery of clustered regularly interspaced short palindromic repeats (CRISPR) activation machinery to modulate both viral and host gene transcription. These findings offer potential for the development of a range of nucleic acid-based T cell therapeutics. |
| format | Article |
| id | doaj-art-d9be359fb83641d7b2450e4ec6560fd2 |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-d9be359fb83641d7b2450e4ec6560fd22025-08-20T03:16:51ZengNature PortfolioNature Communications2041-17232025-05-0116111210.1038/s41467-025-60001-2Efficient mRNA delivery to resting T cells to reverse HIV latencyPaula M. Cevaal0Stanislav Kan1Bridget M. Fisher2Michael A. Moso3Abigail Tan4Haiyin Liu5Abdalla Ali6Kiho Tanaka7Rory A. Shepherd8Youry Kim9Jesslyn Ong10Denzil L. Furtado11Marvin Holz12Damian F. J. Purcell13Joshua M. L. Casan14Thomas Payne15Wei Zhao16Mohamed Fareh17James H. McMahon18Steven G. Deeks19Rebecca Hoh20Sushama Telwatte21Colin W. Pouton22Angus P. R. Johnston23Frank Caruso24Jori Symons25Sharon R. Lewin26Michael Roche27Department of Infectious Diseases, The University of Melbourne at The Peter Doherty Institute for Infection and ImmunityDepartment of Infectious Diseases, The University of Melbourne at The Peter Doherty Institute for Infection and ImmunityDepartment of Infectious Diseases, The University of Melbourne at The Peter Doherty Institute for Infection and ImmunityDepartment of Infectious Diseases, The University of Melbourne at The Peter Doherty Institute for Infection and ImmunityDepartment of Infectious Diseases, The University of Melbourne at The Peter Doherty Institute for Infection and ImmunityMonash Institute of Pharmaceutical Sciences, Monash UniversityDepartment of Infectious Diseases, The University of Melbourne at The Peter Doherty Institute for Infection and ImmunityDepartment of Infectious Diseases, The University of Melbourne at The Peter Doherty Institute for Infection and ImmunityDepartment of Infectious Diseases, The University of Melbourne at The Peter Doherty Institute for Infection and ImmunityDepartment of Infectious Diseases, The University of Melbourne at The Peter Doherty Institute for Infection and ImmunityDepartment of Infectious Diseases, The University of Melbourne at The Peter Doherty Institute for Infection and ImmunityDepartment of Chemical Engineering, The University of MelbourneDepartment of Microbiology and Immunology, The University of Melbourne at The Peter Doherty Institute for Infection and ImmunityDepartment of Microbiology and Immunology, The University of Melbourne at The Peter Doherty Institute for Infection and ImmunityCancer Immunology Program, Peter MacCallum Cancer CentreMonash Institute of Pharmaceutical Sciences, Monash UniversityDepartment of Infectious Diseases, The University of Melbourne at The Peter Doherty Institute for Infection and ImmunityCancer Immunology Program, Peter MacCallum Cancer CentreDepartment of Infectious Diseases, Alfred Hospital and Monash UniversityDepartment of Medicine, University of California, San FranciscoDepartment of Medicine, University of California, San FranciscoDepartment of Infectious Diseases, The University of Melbourne at The Peter Doherty Institute for Infection and ImmunityMonash Institute of Pharmaceutical Sciences, Monash UniversityMonash Institute of Pharmaceutical Sciences, Monash UniversityDepartment of Chemical Engineering, The University of MelbourneTranslational Virology, Department of Medical Microbiology, University Medical CenterDepartment of Infectious Diseases, The University of Melbourne at The Peter Doherty Institute for Infection and ImmunityDepartment of Infectious Diseases, The University of Melbourne at The Peter Doherty Institute for Infection and ImmunityAbstract A major hurdle to curing HIV is the persistence of integrated proviruses in resting CD4+ T cells that remain in a transcriptionally silent, latent state. One strategy to eradicate latent HIV is to activate viral transcription, followed by elimination of infected cells through virus-mediated cytotoxicity or immune-mediated clearance. We hypothesised that mRNA-lipid nanoparticle (LNP) technology would provide an opportunity to deliver mRNA encoding proteins able to reverse HIV latency in resting CD4+ T cells. Here we develop an LNP formulation (LNP X) with unprecedented potency to deliver mRNA to hard-to-transfect resting CD4+ T cells in the absence of cellular toxicity or activation. Encapsulating an mRNA encoding the HIV Tat protein, an activator of HIV transcription, LNP X enhances HIV transcription in ex vivo CD4+ T cells from people living with HIV. LNP X further enables the delivery of clustered regularly interspaced short palindromic repeats (CRISPR) activation machinery to modulate both viral and host gene transcription. These findings offer potential for the development of a range of nucleic acid-based T cell therapeutics.https://doi.org/10.1038/s41467-025-60001-2 |
| spellingShingle | Paula M. Cevaal Stanislav Kan Bridget M. Fisher Michael A. Moso Abigail Tan Haiyin Liu Abdalla Ali Kiho Tanaka Rory A. Shepherd Youry Kim Jesslyn Ong Denzil L. Furtado Marvin Holz Damian F. J. Purcell Joshua M. L. Casan Thomas Payne Wei Zhao Mohamed Fareh James H. McMahon Steven G. Deeks Rebecca Hoh Sushama Telwatte Colin W. Pouton Angus P. R. Johnston Frank Caruso Jori Symons Sharon R. Lewin Michael Roche Efficient mRNA delivery to resting T cells to reverse HIV latency Nature Communications |
| title | Efficient mRNA delivery to resting T cells to reverse HIV latency |
| title_full | Efficient mRNA delivery to resting T cells to reverse HIV latency |
| title_fullStr | Efficient mRNA delivery to resting T cells to reverse HIV latency |
| title_full_unstemmed | Efficient mRNA delivery to resting T cells to reverse HIV latency |
| title_short | Efficient mRNA delivery to resting T cells to reverse HIV latency |
| title_sort | efficient mrna delivery to resting t cells to reverse hiv latency |
| url | https://doi.org/10.1038/s41467-025-60001-2 |
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