Targeting the latent cytomegalovirus reservoir with an antiviral fusion toxin protein

Nature Communications

Volumn 8, Issue , 2017, Pages

  Krishna, B A ^a   Spiess, K ^b   Poole, E L ^a   Lau, B ^a   Voigt, S ^c,d   Kledal, T N ^e,f   Rosenkilde, M M ^b   Sinclair, J H ^a  

^a UNIVERSITY OF CAMBRIDGE   (United Kingdom)

^b UNIVERSITY OF COPENHAGEN   (Denmark)

^c ROBERT KOCH INSTITUTE   (Germany)

^d CHARITÉ UNIVERSITÄTSMEDIZIN BERLIN   (Germany)

^e TECHNICAL UNIVERSITY OF DENMARK   (Denmark)

^f MRC UNIVERSITY OF GLASGOW CENTRE FOR VIRUS RESEARCH   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

CD34 ANTIGEN; CYTOTOXIN; F49A FTP FUSION TOXIN PROTEIN; HYBRID PROTEIN; UNCLASSIFIED DRUG; CHEMOKINE; CHEMOKINE RECEPTOR; FUSION PROTEIN; LIPOPOLYSACCHARIDE RECEPTOR; US28 RECEPTOR, CYTOMEGALOVIRUS; VIRAL PROTEIN;

BIOTECHNOLOGY; CELLS AND CELL COMPONENTS; CHEMICAL BINDING; EXPERIMENTAL STUDY; PROTEIN; REACTIVATION; RESERVOIR; TOXIN; VIRAL DISEASE; VIRUS;

ARTICLE; CELL KILLING; CELL SURFACE; CONTROLLED STUDY; CYTOMEGALOVIRUS INFECTION; GENE EXPRESSION; HUMAN; HUMAN CELL; IN VITRO STUDY; LATENT VIRUS INFECTION; MONOCYTE; NONHUMAN; STEM CELL; TARGET CELL; US28 GENE; VIRUS GENE; VIRUS LOAD; VIRUS REACTIVATION; CELL CULTURE; CELL DEATH; CYTOMEGALOVIRUS; DISEASE CARRIER; ENDOCYTOSIS; GENETICS; HEMATOPOIETIC STEM CELL TRANSPLANTATION; IMMUNOLOGY; ISOLATION AND PURIFICATION; METABOLISM; PATHOGENICITY; VIROLOGY; VIRUS ACTIVATION; VIRUS LATENCY;

CYTOMEGALOVIRUS; HUMAN HERPESVIRUS 5;

ANTIGENS, CD34; CELL DEATH; CELLS, CULTURED; CHEMOKINES; CYTOMEGALOVIRUS; DISEASE RESERVOIRS; ENDOCYTOSIS; GENES, VIRAL; HEMATOPOIETIC STEM CELL TRANSPLANTATION; HUMANS; LIPOPOLYSACCHARIDE RECEPTORS; MONOCYTES; RECEPTORS, CHEMOKINE; RECOMBINANT FUSION PROTEINS; STEM CELLS; VIRAL LOAD; VIRAL PROTEINS; VIRUS ACTIVATION; VIRUS LATENCY;

EID: 85011361630     PISSN: None     EISSN: 20411723     Source Type: Journal    
DOI: 10.1038/ncomms14321     Document Type: Article

References (62)

1. Rook, A. H. Interactions of cytomegalovirus with the human immune system. Rev. Infect. Dis. 10, S460-S467 (1988).
2. Cannon, M. J. Congenital cytomegalovirus (CMV) epidemiology and awareness. J. Clin. Virol. 46, S6-S10 (2009).
3. Poole, E. et al. Alveolar macrophages isolated directly from human cytomegalovirus (HCMV)-seropositive individuals are sites of HCMV reactivation in vivo. J. Infect. Dis. 211, 1936-1942 (2015).
4. Sinclair, J. & Sissons, P. Latency and reactivation of human cytomegalovirus. J. Gen. Virol. 87, 1763-1779 (2006).
5. Wills, M. R., Poole, E., Lau, B., Krishna, B. & Sinclair., J. H. The immunology of human cytomegalovirus latency: could latent infection be cleared by novel immunotherapeutic strategies? Cell Mol. Immunol. 12, 128-138 (2015).
6. Taylor-Wiedeman, J., Sissons, P. & Sinclair, J. Induction of endogenous human cytomegalovirus gene expression after differentiation of monocytes from healthy carriers. J. Virol. 68, 1597-1604 (1994).
7. Reeves, M. B., MacAry, P. A., Lehner, P. J., Sissons, J. G. & Sinclair, J. H. Latency, chromatin remodeling, and reactivation of human cytomegalovirus in the dendritic cells of healthy carriers. Proc. Natl Acad. Sci. USA 102, 4140-4145 (2005).
8. Söderberg-Nauclér, C. et al. Reactivation of latent human cytomegalovirus in CD14+ monocytes is differentiation dependent. J. Virol. 75, 7543-7554 (2001).
9. Weekes, M. P. et al. Latency-Associated degradation of the MRP1 drug transporter during latent human cytomegalovirus infection. Science 340, 199-202 (2013).
10. Poole, E., Dallas, S. R. M., Colston, J., Joseph, R. S. & Sinclair, J. Virally induced changes in cellular microRNAs maintain latency of human cytomegalovirus in CD34(+) progenitors. J. Gen. Virol. 92, 1539-1549 (2011).
11. Avdic, S., Cao, J. Z., Cheung, A. K., Abendroth, A. & Slobedman., B. Viral interleukin-10 expressed by human cytomegalovirus during the latent phase of infection modulates latently infected myeloid cell differentiation. J. Virol. 85, 7465-7471 (2011).
12. Poole, E. et al. Latency-Associated viral interleukin-10 (IL-10) encoded by human cytomegalovirus modulates cellular IL-10 and CCL8 secretion during latent infection through changes in the cellular microRNA hsa-miR-92a. J. Virol. 88, 13947-13955 (2014).
13. Slobedman, B. & Cheung, A. K. Microarrays for the study of viral gene expression during human cytomegalovirus latent infection. Clin. Bioinformatics 141, 153-175 (2008).
14. Mason, G. M., Poole, E., Sissons, J. G., Wills, M. R. & Sinclair, J. H. Human cytomegalovirus latency alters the cellular secretome, inducing cluster of differentiation (CD)4+ T-cell migration and suppression of effector function. Proc. Natl Acad. Sci. USA 109, 14538-14543 (2012).
15. Reeves, M. & Sinclair, J. Regulation of human cytomegalovirus transcription in latency: beyond the major immediate-early promoter. Viruses 5, 1395-1413 (2013).
16. Poole, E. & Sinclair, J. Sleepless latency of human cytomegalovirus. Med. Microbiol. Immunol. 204, 421-429 (2015).
17. Sinclair, J. H. & Reeves, M. B. Human cytomegalovirus manipulation of latently infected cells. Viruses 5, 2803-2824 (2013).
18. Rossetto, C. C., Tarrant-Elorza, M. & Pari., G. S. Cis and trans acting factors involved in human cytomegalovirus experimental and natural latent infection of CD14 (+) monocytes and CD34 (+) cells. PLoS Pathog. 9, e1003366 (2013).
19. Tarrant-Elorza, M., Rossetto, C. C. & Pari, G. S. Maintenance and replication of the human cytomegalovirus genome during latency. Cell Host Microbe 16, 43-54 (2014).
20. Slobedman, B. et al. Human cytomegalovirus latent infection and associated viral gene expression. Future Microbiol. 5, 883-900 (2010).
21. Takenaka, K. et al. Cytomegalovirus reactivation after allogeneic hematopoietic stem cell transplantation is associated with a reduced risk of relapse in patients with acute myeloid leukemia who survived to day 100 after transplantation: The Japan Society for Hematopoietic Cell Transplantation Transplantation-related Complication Working Group. Biol. Blood and Marrow Transplant. 21, 2008-2016 (2015).
22. Nichols, W. G., Corey, L., Gooley, T., Davis, C. & Boeckh, M. High risk of death due to bacterial and fungal infection among cytomegalovirus (CMV)-seronegative recipients of stem cell transplants from seropositive donors: evidence for indirect effects of primary CMV infection. J. Infect. Dis. 185, 273-282 (2002).
23. Boeckh, M. & Nichols., W. G. The impact of cytomegalovirus serostatus of donor and recipient before hematopoietic stem cell transplantation in the era of antiviral prophylaxis and preemptive therapy. Blood 103, 2003-2008 (2004).
24. Boeckh, M. et al. Cytomegalovirus in hematopoietic stem cell transplant recipients: current status, known challenges, and future strategies. Biol. Blood Marrow Transplant. 9, 543-558 (2003).
25. Ljungman, P., Hakki, M. & Boeckh, M. Cytomegalovirus in hematopoietic stem cell transplant recipients. Infect. Dis. Clin. North Am. 24, 319-337 (2010).
26. Ljungman, P. et al. Management of CMV, HHV-6, HHV-7 and Kaposisarcoma herpesvirus (HHV-8) infections in patients with hematological malignancies and after SCT. Bone Marrow Transplant. 42, 227-240 (2008).
27. Boeckh, M. & Ljungman, P. How we treat cytomegalovirus in hematopoietic cell transplant recipients. Blood 113, 5711-5719 (2009).
28. Chee, M. S. et al. Analysis of the protein-coding content of the sequence of human cytomegalovirus strain AD169. Curr. Top. Microbiol. Immunol. 154, 125-169 (1990).
29. Welch, A. R., McGregor, L. M. & Gibson, W. Cytomegalovirus homologs of cellular G protein-coupled receptor genes are transcribed. J. Virol. 65, 3915-3918 (1991).
30. Margulies, B. J., Browne, H. & Gibson, W. Identification of the human cytomegalovirus G protein-coupled receptor homologue encoded by UL33 in infected cells and enveloped virus particles. Virology 225, 111-125 (1996).
31. Goodrum, F. D., Jordan, C. T., High, K. & Shenk, T. Human cytomegalovirus gene expression during infection of primary hematopoietic progenitor cells: A model for latency. Proc. Natl Acad. Sci. USA 99, 16255-16260 (2002).
32. Cheung, A. K., Abendroth, A., Cunningham, A. L. & Slobedman, B. Viral gene expression during the establishment of human cytomegalovirus latent infection in myeloid progenitor cells. Blood 108, 3691-3699 (2006).
33. Beisser, P. S., Laurent, L., Virelizier, J. L. & Michelson, S. Human cytomegalovirus chemokine receptor gene US28 is transcribed in latently infected THP-1 monocytes. J. Virol. 75, 5949-5957 (2001).
34. Poole, E. et al. The myeloid transcription factor GATA-2 regulates the viral UL144 gene during human cytomegalovirus latency in an isolate-specific manner. J. Virol. 87, 4261-4271 (2013).
35. Humby, M. S. & OConnor, C. M. HCMV US28 is important for latent infection of hemtopoietic progenitor cells. J. Virol. 90, 2959-2970 (2016).
36. Kledal, T. N., Rosenkilde, M. M. & Schwartz, T. W. Selective recognition of the membrane-bound CX3C chemokine, fractalkine, by the human cytomegalovirus-encoded broad-spectrum receptor US28. FEBS Lett. 441, 209-214 (1998).
37. Vomaske, J., Nelson, J. A. & Streblow, D. N. Human cytomegalovirus US28: A functionally selective chemokine binding receptor. Infect. Disord. Drug Targets 9, 548 (2009).
38. McLean, K. A., Holst, P. J., Martini, L., Schwartz, T. W. & Rosenkilde, M. M. Similar activation of signal transduction pathways by the herpesvirus-encoded chemokine receptors US28 and ORF74. Virology 325, 241-251 (2004).
39. Streblow, D. N. et al. The human cytomegalovirus chemokine receptor US28 mediates vascular smooth muscle cell migration. Cell 99, 511-520 (1999).
40. Streblow, D. N. et al. Human cytomegalovirus chemokine receptor US28-induced smooth muscle cell migration is mediated by focal adhesion kinase and Src. J. Biol. Chem. 278, 50456-50465 (2003).
41. Vischer, H. F., Siderius, M., Leurs, R. & Smit., M. J. Herpesvirus-encoded GPCRs: neglected players in inflammatory and proliferative diseases? Nat. Rev. Drug Discov. 13, 123-139 (2014).
42. Tschische, P., Tadagaki, K., Kamal, M., Jockers, R. & Waldhoer, M. Heteromerization of human cytomegalovirus encoded chemokine receptors. Biochem. Pharmacol. 82, 610-619 (2011).
43. Wayne, A. S., FitzGerald, D. J., Kreitman, R. J. & Pastan, I. Immunotoxins for leukemia. Blood 123, 2470-2477 (2014).
44. Choudhary, S., Mathew, M. & Verma, R. S. Therapeutic potential of anticancer immunotoxins. Drug Discov. Today 16, 495-503 (2011).
45. Spiess, K., Jakobsen, M. H., Kledal, T. N. & Rosenkilde., M. M. The future of antiviral immunotoxins. J. Leukoc. Biol. 99, 911-925 (2016).
46. Spiess, K. et al. Rationally designed chemokine-based toxin targeting the viral G protein-coupled receptor US28 potently inhibits cytomegalovirus infection in vivo. Proc. Natl Acad. Sci. USA 112, 8427-8432 (2015).
47. Sinclair, J., Baillie, J., Bryant, L., Taylor-Wiedeman, J. & Sissons, J. Repression of human cytomegalovirus major immediate early gene expression in a monocytic cell line. J. Gen. Virol. 73, 433-435 (1992).
48. Keyes, L. R. et al. HCMV protein LUNA is required for viral reactivation from latently infected primary CD14+ cells. PLoS ONE 7, e52827 (2012).
49. Hargett, D. & Shenk, T. E. Experimental human cytomegalovirus latency in CD14+ monocytes. Proc. Natl Acad. Sci. USA 107, 20039-20044 (2010).
50. OConnor, C. M. & Murphy., E. A. A myeloid progenitor cell line capable of supporting human cytomegalovirus latency and reactivation, resulting in infectious progeny. J. Virol. 86, 9854-9865 (2012).
51. Petrucelli, A., Rak, M., Grainger, L. & Goodrum, F. Characterization of a novel Golgi apparatus-localized latency determinant encoded by human cytomegalovirus. J. Virol. 83, 5615-5629 (2009).
52. Goodrum, F., Reeves, M., Sinclair, J., High, K. & Shenk, T. Human cytomegalovirus sequences expressed in latently infected individuals promote a latent infection in vitro. Blood 110, 937-945 (2007).
53. Reeves, M. B. & Sinclair, J. H. Analysis of latent viral gene expression in natural and experimental latency models of human cytomegalovirus and its correlation with histone modifications at a latent promoter. J. Gen. Virol. 91(Pt 3): 599-604 (2010).
54. Krishna, B. et al. Transient activation of human cytomegalovirus lytic gene expression during latency allows cytotoxic T cell killing of latently infected cells. Sci. Rep. 6, 24674 (2016).
55. Lau, B. et al. The expression of human cytomegalovirus microRNA MiRUL148D during latent infection in primary myeloid cells inhibits activin A-Triggered secretion of IL-6. Sci. Rep. 6, 31205 (2016).
56. Steen, A. et al. Biased and constitutive signaling in the CC-chemokine receptor CCR5 by manipulating the interface between transmembrane helices 6 and 7. J. Biol. Chem. 288, 12511-12521 (2013).
57. Burg, J. S. et al. Structural basis for chemokine recognition and activation of a viral G protein-coupled receptor. Science 347, 1113-1117 (2015).
58. Poole, E., Reeves, M. & Sinclair., J. H. The use of primary human cells (fibroblasts, monocytes, and others) to assess human cytomegalovirus function. Methods Mol. Biol. 1119, 81-98 (2014).
59. Reeves, M. B., Lehner, P. J., Sissons, J. G. P. & Sinclair, J. H. An in vitro model for the regulation of human cytomegalovirus latency and reactivation in dendritic cells by chromatin remodelling. J. Gen. Virol. 86, 2949-2954 (2005).
60. Maussang, D. et al. Human cytomegalovirus-encoded chemokine receptor US28 promotes tumorigenesis. Proc. Natl Acad. Sci. USA 103, 13068-13073 (2006).
61. Poole, E. et al. Identification of TRIM23 as a cofactor involved in the regulation of NF-kB by human cytomegalovirus. J. Virol. 83, 3581-3590 (2009).
62. Rosenkilde, M. M., Andersen, M. B., Nygaard, R., Frimurer, T. M. & Schwartz, T. W. Activation of the CXCR3 chemokine receptor through anchoring of a small molecule chelator ligand between TM-III,-IV, and-VI. Mol. Pharmacol. 71, 930-941 (2007).