{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,13]],"date-time":"2026-02-13T20:51:57Z","timestamp":1771015917828,"version":"3.50.1"},"reference-count":36,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2024,9,24]],"date-time":"2024-09-24T00:00:00Z","timestamp":1727136000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000265","name":"British Medical Research Council","doi-asserted-by":"publisher","award":["G0701279"],"award-info":[{"award-number":["G0701279"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"British Medical Research Council","doi-asserted-by":"publisher","award":["PKCS"],"award-info":[{"award-number":["PKCS"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"British Medical Research Council","doi-asserted-by":"publisher","award":["DZIF MD programme TI 07.003"],"award-info":[{"award-number":["DZIF MD programme TI 07.003"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000735","name":"University of Cambridge","doi-asserted-by":"publisher","award":["G0701279"],"award-info":[{"award-number":["G0701279"]}],"id":[{"id":"10.13039\/501100000735","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000735","name":"University of Cambridge","doi-asserted-by":"publisher","award":["PKCS"],"award-info":[{"award-number":["PKCS"]}],"id":[{"id":"10.13039\/501100000735","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000735","name":"University of Cambridge","doi-asserted-by":"publisher","award":["DZIF MD programme TI 07.003"],"award-info":[{"award-number":["DZIF MD programme TI 07.003"]}],"id":[{"id":"10.13039\/501100000735","id-type":"DOI","asserted-by":"publisher"}]},{"name":"German Center for Infection Research","award":["G0701279"],"award-info":[{"award-number":["G0701279"]}]},{"name":"German Center for Infection Research","award":["PKCS"],"award-info":[{"award-number":["PKCS"]}]},{"name":"German Center for Infection Research","award":["DZIF MD programme TI 07.003"],"award-info":[{"award-number":["DZIF MD programme TI 07.003"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pathogens"],"abstract":"<jats:p>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 \u2018shock-and-kill\u2019 strategy to target the latent HCMV reservoir in myeloid cells.<\/jats:p>","DOI":"10.3390\/pathogens13100821","type":"journal-article","created":{"date-parts":[[2024,9,24]],"date-time":"2024-09-24T10:41:47Z","timestamp":1727174507000},"page":"821","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Virus-Specific Nanobody-Chimeras Degrade the Human Cytomegalovirus US28 Protein in CD34+ Cells"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3904-6121","authenticated-orcid":false,"given":"Emma","family":"Poole","sequence":"first","affiliation":[{"name":"Department of Medicine, University of Cambridge, Addenbrooke\u2019s Hospital, Hills Road, Cambridge CB2 0QQ, UK"},{"name":"Department of Pathology, Division of Virology, University of Cambridge, Addenbrooke\u2019s Hospital, Hills Road, Cambridge CB2 2QQ, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Janika","family":"Schmitt","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Cambridge, Addenbrooke\u2019s Hospital, Hills Road, Cambridge CB2 0QQ, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4547-4034","authenticated-orcid":false,"given":"Stephen C.","family":"Graham","sequence":"additional","affiliation":[{"name":"Department of Pathology, Division of Virology, University of Cambridge, Addenbrooke\u2019s Hospital, Hills Road, Cambridge CB2 2QQ, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2666-6268","authenticated-orcid":false,"given":"Bernard T.","family":"Kelly","sequence":"additional","affiliation":[{"name":"Cambridge Institute for Medical Research, Keith Peters Building, Hills Road, Cambridge CB2 0XY, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2616-9571","authenticated-orcid":false,"given":"John","family":"Sinclair","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Cambridge, Addenbrooke\u2019s Hospital, Hills Road, Cambridge CB2 0QQ, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,9,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1038\/s41579-021-00582-z","article-title":"Pathogenesis of human cytomegalovirus in the immunocompromised host","volume":"19","author":"Griffiths","year":"2021","journal-title":"Nat. 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