Virus-specific nanobody-chimeras degrade the human cytomegalovirus US28 protein in CD34+ cells
After primary infection, human cytomegalovirus (HCMV) establishes lifelong persistence, underpinned by latent carriage of the virus with spontaneous reactivation events. In the immune-competent, primary infection or reactivation from latency rarely causes disease. However, HCMV can cause significant...
Gespeichert in:
| Hauptverfasser: | , , , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
24 September 2024
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| In: |
Pathogens
Year: 2024, Jahrgang: 13, Heft: 10, Pages: 1-10 |
| ISSN: | 2076-0817 |
| DOI: | 10.3390/pathogens13100821 |
| Online-Zugang: | Verlag, kostenfrei, Volltext: https://doi.org/10.3390/pathogens13100821
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| Verfasserangaben: | Emma Poole, Janika Schmitt, Stephen C. Graham, Bernard T. Kelly and John Sinclair |
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| 245 | 1 | 0 | |a Virus-specific nanobody-chimeras degrade the human cytomegalovirus US28 protein in CD34+ cells |c Emma Poole, Janika Schmitt, Stephen C. Graham, Bernard T. Kelly and John Sinclair |
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| 520 | |a After primary infection, human cytomegalovirus (HCMV) establishes lifelong persistence, underpinned by latent carriage of the virus with spontaneous reactivation events. In the immune-competent, primary infection or reactivation from latency rarely causes disease. However, HCMV can cause significant disease in immune-compromised individuals such as immune-suppressed transplant patients. Latency, where the viral genome is carried in the absence of the production of infectious virions, can be established in undifferentiated cells of the myeloid lineage. A number of stimuli can cause virus reactivation from latency to occur, beginning with the induction of viral immediate-early (IE) lytic gene expression. The suppression of viral IE gene expression to establish and maintain latent infection is known to result from a balance of viral and cellular factors. One key viral factor involved in this is the G protein-coupled receptor US28. Recently, we have shown that US28 is targeted for degradation by a modified nanobody (PCTD-Vun100bv) based on the novel PACTAC (PCSK9-antibody clearance-targeting chimeras) approach for targeted protein degradation. Furthermore, we have shown that this PCTD-Vun100bv-induced degradation of US28 results in IE gene expression in experimentally latently infected CD14+ monocytes. However, HCMV also establishes latency in CD34+ bone marrow cells, the progenitors of CD14+ cells. Here, we show that PCTD-Vun100bv also causes US28 degradation in these CD34+ primary cells, again resulting in the induction of viral IE gene expression. Additionally, we show that PCTD-Vun100bv can target US28 in naturally latently infected CD14+ monocytes from an HCMV-seropositive donor, allowing these latently infected cells to be killed by HCMV-specific cytotoxic T cells from that same donor. These observations support the view that targeting US28 for degradation during natural latency could be a tractable 'shock-and-kill' strategy to target the latent HCMV reservoir in myeloid cells. | ||
| 650 | 4 | |a Antigens, CD34 | |
| 650 | 4 | |a Cytomegalovirus | |
| 650 | 4 | |a Cytomegalovirus Infections | |
| 650 | 4 | |a human cytomegalovirus | |
| 650 | 4 | |a Humans | |
| 650 | 4 | |a latency | |
| 650 | 4 | |a nanobodies | |
| 650 | 4 | |a Proteolysis | |
| 650 | 4 | |a proteostasis | |
| 650 | 4 | |a Receptors, Chemokine | |
| 650 | 4 | |a Single-Domain Antibodies | |
| 650 | 4 | |a targeted degradation | |
| 650 | 4 | |a Viral Proteins | |
| 650 | 4 | |a Virus Activation | |
| 650 | 4 | |a Virus Latency | |
| 700 | 1 | |a Schmitt, Janika |e VerfasserIn |0 (DE-588)1345934726 |0 (DE-627)1906766010 |4 aut | |
| 700 | 1 | |a Graham, Stephen C. |e VerfasserIn |4 aut | |
| 700 | 1 | |a Kelly, Bernard T. |e VerfasserIn |4 aut | |
| 700 | 1 | |a Sinclair, John |e VerfasserIn |4 aut | |
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