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. 1990 Sep;64(9):4598–4602. doi: 10.1128/jvi.64.9.4598-4602.1990

T-cell activation is required for efficient replication of human herpesvirus 6.

N Frenkel 1, E C Schirmer 1, G Katsafanas 1, C H June 1
PMCID: PMC247937  PMID: 2166835

Abstract

We have investigated whether T-cell activation is required for the replication of the T-lymphotropic human herpesvirus 6. The virus did not replicate in quiescent peripheral blood lymphocytes but replicated efficiently following exposure of the cells to the polyclonal mitogen phytohemagglutinin (PHA). When purified T cells were treated with PHA in the absence of accessory cells, no virus replication was observed unless exogenous interleukin-2 (IL-2) was added to the medium, promoting cell division. Incubation of peripheral blood lymphocytes in the absence of PHA but in the presence of IL-2 resulted in delayed cell blastogenesis and virus replication. Cell blastogenesis and virus replication did not occur in the purified T-cell cultures incubated with IL-2 alone. Taken together, the results show that human herpesvirus 6 replication requires full progression of the cell cycle. This finding might have implications for the pathogenicity of the virus in the human host.

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Selected References

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  1. Ablashi D. V., Lusso P., Hung C. L., Salahuddin S. Z., Josephs S. F., Llana T., Kramarsky B., Biberfeld P., Markham P. D., Gallo R. C. Utilization of human hematopoietic cell lines for the propagation and characterization of HBLV (human herpesvirus 6). Int J Cancer. 1988 Nov 15;42(5):787–791. doi: 10.1002/ijc.2910420526. [DOI] [PubMed] [Google Scholar]
  2. Agut H., Guetard D., Collandre H., Dauguet C., Montagnier L., Miclea J. M., Baurmann H., Gessain A. Concomitant infection by human herpesvirus 6, HTLV-I, and HIV-2. Lancet. 1988 Mar 26;1(8587):712–712. doi: 10.1016/s0140-6736(88)91520-6. [DOI] [PubMed] [Google Scholar]
  3. Becker W. B., Engelbrecht S., Becker M. L., Piek C., Robson B. A., Wood L., Jacobs P. New T-lymphotropic human herpesviruses. Lancet. 1989 Jan 7;1(8628):41–41. doi: 10.1016/s0140-6736(89)91691-7. [DOI] [PubMed] [Google Scholar]
  4. Black J. B., Sanderlin K. C., Goldsmith C. S., Gary H. E., Lopez C., Pellett P. E. Growth properties of human herpesvirus-6 strain Z29. J Virol Methods. 1989 Nov;26(2):133–145. doi: 10.1016/0166-0934(89)90143-2. [DOI] [PubMed] [Google Scholar]
  5. Braun R. W., Reiser H. C. Replication of human cytomegalovirus in human peripheral blood T cells. J Virol. 1986 Oct;60(1):29–36. doi: 10.1128/jvi.60.1.29-36.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Brown N. A., Sumaya C. V., Liu C. R., Ench Y., Kovacs A., Coronesi M., Kaplan M. H. Fall in human herpesvirus 6 seropositivity with age. Lancet. 1988 Aug 13;2(8607):396–396. doi: 10.1016/s0140-6736(88)92864-4. [DOI] [PubMed] [Google Scholar]
  7. Buchbinder A., Josephs S. F., Ablashi D., Salahuddin S. Z., Klotman M. E., Manak M., Krueger G. R., Wong-Staal F., Gallo R. C. Polymerase chain reaction amplification and in situ hybridization for the detection of human B-lymphotropic virus. J Virol Methods. 1988 Sep;21(1-4):191–197. doi: 10.1016/0166-0934(88)90065-1. [DOI] [PubMed] [Google Scholar]
  8. Böhnlein E., Lowenthal J. W., Siekevitz M., Ballard D. W., Franza B. R., Greene W. C. The same inducible nuclear proteins regulates mitogen activation of both the interleukin-2 receptor-alpha gene and type 1 HIV. Cell. 1988 Jun 3;53(5):827–836. doi: 10.1016/0092-8674(88)90099-2. [DOI] [PubMed] [Google Scholar]
  9. Damle N. K., Mohagheghpour N., Hansen J. A., Engleman E. G. Alloantigen-specific cytotoxic and suppressor T lymphocytes are derived from phenotypically distinct precursors. J Immunol. 1983 Nov;131(5):2296–2300. [PubMed] [Google Scholar]
  10. Downing R. G., Sewankambo N., Serwadda D., Honess R., Crawford D., Jarrett R., Griffin B. E. Isolation of human lymphotropic herpesviruses from Uganda. Lancet. 1987 Aug 15;2(8555):390–390. doi: 10.1016/s0140-6736(87)92403-2. [DOI] [PubMed] [Google Scholar]
  11. Frenkel N., Schirmer E. C., Wyatt L. S., Katsafanas G., Roffman E., Danovich R. M., June C. H. Isolation of a new herpesvirus from human CD4+ T cells. Proc Natl Acad Sci U S A. 1990 Jan;87(2):748–752. doi: 10.1073/pnas.87.2.748. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Gowda S. D., Stein B. S., Mohagheghpour N., Benike C. J., Engleman E. G. Evidence that T cell activation is required for HIV-1 entry in CD4+ lymphocytes. J Immunol. 1989 Feb 1;142(3):773–780. [PubMed] [Google Scholar]
  13. Greene W. C., Böhnlein E., Ballard D. W. HIV-1, HTLV-1 and normal T-cell growth: transcriptional strategies and surprises. Immunol Today. 1989 Aug;10(8):272–278. doi: 10.1016/0167-5699(89)90141-2. [DOI] [PubMed] [Google Scholar]
  14. Horvat R. T., Wood C., Balachandran N. Transactivation of human immunodeficiency virus promoter by human herpesvirus 6. J Virol. 1989 Feb;63(2):970–973. doi: 10.1128/jvi.63.2.970-973.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Hunninghake G. W., Monick M. M., Liu B., Stinski M. F. The promoter-regulatory region of the major immediate-early gene of human cytomegalovirus responds to T-lymphocyte stimulation and contains functional cyclic AMP-response elements. J Virol. 1989 Jul;63(7):3026–3033. doi: 10.1128/jvi.63.7.3026-3033.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. June C. H., Ledbetter J. A., Gillespie M. M., Lindsten T., Thompson C. B. T-cell proliferation involving the CD28 pathway is associated with cyclosporine-resistant interleukin 2 gene expression. Mol Cell Biol. 1987 Dec;7(12):4472–4481. doi: 10.1128/mcb.7.12.4472. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Kehrl J. H., Dukovich M., Whalen G., Katz P., Fauci A. S., Greene W. C. Novel interleukin 2 (IL-2) receptor appears to mediate IL-2-induced activation of natural killer cells. J Clin Invest. 1988 Jan;81(1):200–205. doi: 10.1172/JCI113295. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Krueger G. R., Ablashi D. V. Human B-lymphotropic virus in Germany. Lancet. 1987 Sep 19;2(8560):694–694. doi: 10.1016/s0140-6736(87)92490-1. [DOI] [PubMed] [Google Scholar]
  19. Linde A., Dahl H., Wahren B., Fridell E., Salahuddin Z., Biberfeld P. IgG antibodies to human herpesvirus-6 in children and adults and in primary Epstein-Barr virus infections and cytomegalovirus infections [corrected]. J Virol Methods. 1988 Sep;21(1-4):117–123. doi: 10.1016/0166-0934(88)90058-4. [DOI] [PubMed] [Google Scholar]
  20. Lopez C., Pellett P., Stewart J., Goldsmith C., Sanderlin K., Black J., Warfield D., Feorino P. Characteristics of human herpesvirus-6. J Infect Dis. 1988 Jun;157(6):1271–1273. doi: 10.1093/infdis/157.6.1271. [DOI] [PubMed] [Google Scholar]
  21. Lusso P., Ensoli B., Markham P. D., Ablashi D. V., Salahuddin S. Z., Tschachler E., Wong-Staal F., Gallo R. C. Productive dual infection of human CD4+ T lymphocytes by HIV-1 and HHV-6. Nature. 1989 Jan 26;337(6205):370–373. doi: 10.1038/337370a0. [DOI] [PubMed] [Google Scholar]
  22. Lusso P., Markham P. D., Tschachler E., di Marzo Veronese F., Salahuddin S. Z., Ablashi D. V., Pahwa S., Krohn K., Gallo R. C. In vitro cellular tropism of human B-lymphotropic virus (human herpesvirus-6). J Exp Med. 1988 May 1;167(5):1659–1670. doi: 10.1084/jem.167.5.1659. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Margolick J. B., Volkman D. J., Folks T. M., Fauci A. S. Amplification of HTLV-III/LAV infection by antigen-induced activation of T cells and direct suppression by virus of lymphocyte blastogenic responses. J Immunol. 1987 Mar 15;138(6):1719–1723. [PubMed] [Google Scholar]
  24. McDougal J. S., Mawle A., Cort S. P., Nicholson J. K., Cross G. D., Scheppler-Campbell J. A., Hicks D., Sligh J. Cellular tropism of the human retrovirus HTLV-III/LAV. I. Role of T cell activation and expression of the T4 antigen. J Immunol. 1985 Nov;135(5):3151–3162. [PubMed] [Google Scholar]
  25. Morris D. J., Littler E., Arrand J. R., Jordan D., Mallick N. P., Johnson R. W. Human herpesvirus 6 infection in renal-transplant recipients. N Engl J Med. 1989 Jun 8;320(23):1560–1561. [PubMed] [Google Scholar]
  26. Nabel G., Baltimore D. An inducible transcription factor activates expression of human immunodeficiency virus in T cells. Nature. 1987 Apr 16;326(6114):711–713. doi: 10.1038/326711a0. [DOI] [PubMed] [Google Scholar]
  27. Niederman J. C., Liu C. R., Kaplan M. H., Brown N. A. Clinical and serological features of human herpesvirus-6 infection in three adults. Lancet. 1988 Oct 8;2(8615):817–819. doi: 10.1016/s0140-6736(88)92783-3. [DOI] [PubMed] [Google Scholar]
  28. Okuno T., Takahashi K., Balachandra K., Shiraki K., Yamanishi K., Takahashi M., Baba K. Seroepidemiology of human herpesvirus 6 infection in normal children and adults. J Clin Microbiol. 1989 Apr;27(4):651–653. doi: 10.1128/jcm.27.4.651-653.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Roffman E., Frenkel N. Interleukin-2 inhibits the replication of human herpesvirus-6 in mature thymocytes. Virology. 1990 Apr;175(2):591–594. doi: 10.1016/0042-6822(90)90447-y. [DOI] [PubMed] [Google Scholar]
  30. Salahuddin S. Z., Ablashi D. V., Markham P. D., Josephs S. F., Sturzenegger S., Kaplan M., Halligan G., Biberfeld P., Wong-Staal F., Kramarsky B. Isolation of a new virus, HBLV, in patients with lymphoproliferative disorders. Science. 1986 Oct 31;234(4776):596–601. doi: 10.1126/science.2876520. [DOI] [PubMed] [Google Scholar]
  31. Sambucetti L. C., Cherrington J. M., Wilkinson G. W., Mocarski E. S. NF-kappa B activation of the cytomegalovirus enhancer is mediated by a viral transactivator and by T cell stimulation. EMBO J. 1989 Dec 20;8(13):4251–4258. doi: 10.1002/j.1460-2075.1989.tb08610.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Saxinger C., Polesky H., Eby N., Grufferman S., Murphy R., Tegtmeir G., Parekh V., Memon S., Hung C. Antibody reactivity with HBLV (HHV-6) in U.S. populations. J Virol Methods. 1988 Sep;21(1-4):199–208. doi: 10.1016/0166-0934(88)90066-3. [DOI] [PubMed] [Google Scholar]
  33. Smith K. A. Interleukin-2: inception, impact, and implications. Science. 1988 May 27;240(4856):1169–1176. doi: 10.1126/science.3131876. [DOI] [PubMed] [Google Scholar]
  34. Stern J. B., Smith K. A. Interleukin-2 induction of T-cell G1 progression and c-myb expression. Science. 1986 Jul 11;233(4760):203–206. doi: 10.1126/science.3523754. [DOI] [PubMed] [Google Scholar]
  35. Suga S., Yoshikawa T., Asano Y., Yazaki T., Hirata S. Human herpesvirus-6 infection (exanthem subitum) without rash. Pediatrics. 1989 Jun;83(6):1003–1006. [PubMed] [Google Scholar]
  36. Takahashi K., Sonoda S., Higashi K., Kondo T., Takahashi H., Takahashi M., Yamanishi K. Predominant CD4 T-lymphocyte tropism of human herpesvirus 6-related virus. J Virol. 1989 Jul;63(7):3161–3163. doi: 10.1128/jvi.63.7.3161-3163.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Tedder R. S., Briggs M., Cameron C. H., Honess R., Robertson D., Whittle H. A novel lymphotropic herpesvirus. Lancet. 1987 Aug 15;2(8555):390–392. doi: 10.1016/s0140-6736(87)92404-4. [DOI] [PubMed] [Google Scholar]
  38. Tong-Starksen S. E., Luciw P. A., Peterlin B. M. Human immunodeficiency virus long terminal repeat responds to T-cell activation signals. Proc Natl Acad Sci U S A. 1987 Oct;84(19):6845–6849. doi: 10.1073/pnas.84.19.6845. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Ueda K., Kusuhara K., Hirose M., Okada K., Miyazaki C., Tokugawa K., Nakayama M., Yamanishi K. Exanthem subitum and antibody to human herpesvirus-6. J Infect Dis. 1989 Apr;159(4):750–752. doi: 10.1093/infdis/159.4.750. [DOI] [PubMed] [Google Scholar]
  40. Ward K. N., Gray J. J., Efstathiou S. Brief report: primary human herpesvirus 6 infection in a patient following liver transplantation from a seropositive donor. J Med Virol. 1989 Jun;28(2):69–72. doi: 10.1002/jmv.1890280203. [DOI] [PubMed] [Google Scholar]
  41. Yamanishi K., Okuno T., Shiraki K., Takahashi M., Kondo T., Asano Y., Kurata T. Identification of human herpesvirus-6 as a causal agent for exanthem subitum. Lancet. 1988 May 14;1(8594):1065–1067. doi: 10.1016/s0140-6736(88)91893-4. [DOI] [PubMed] [Google Scholar]
  42. Yoshikawa T., Suga S., Asano Y., Yazaki T., Kodama H., Ozaki T. Distribution of antibodies to a causative agent of exanthem subitum (human herpesvirus-6) in healthy individuals. Pediatrics. 1989 Oct;84(4):675–677. [PubMed] [Google Scholar]
  43. Zagury D., Bernard J., Leonard R., Cheynier R., Feldman M., Sarin P. S., Gallo R. C. Long-term cultures of HTLV-III--infected T cells: a model of cytopathology of T-cell depletion in AIDS. Science. 1986 Feb 21;231(4740):850–853. doi: 10.1126/science.2418502. [DOI] [PubMed] [Google Scholar]

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