Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1996 Mar 15;97(6):1373–1381. doi: 10.1172/JCI118557

Human herpesvirus-6 enhances natural killer cell cytotoxicity via IL-15.

L Flamand 1, I Stefanescu 1, J Menezes 1
PMCID: PMC507195  PMID: 8617868

Abstract

The marked tropism of human herpesvirus-6 (HHV-6) for natural killer (NK) cells and T lymphocytes has led us to investigate the effect of HHV-6 on cellular cytotoxicity. We describe here how HHV-6 infection of peripheral blood mononuclear cells (PBMC) leads to upregulation of their NK cell cytotoxicity. The induction of NK cell activity by HHV-6 was abrogated by monoclonal antibodies (mAbs) to IL-15 but not by mAbs to other cytokines (IFN-alpha, IFN-gamma, TNF-alpha, TNF-beta, IL-2, IL-12) suggesting that IL-15 secreted in response to viral infection was responsible for the observed effect. Furthermore, NK activation by HHV-6 was blocked with mAb to CD122, as well as by human anti-HHV-6 neutralizing antibodies. Using RT-PCR, we were able to detect IL-15 mRNA upregulation in purified monocyte and NK cell preparations. IL-15 protein synthesis was increased in response to HHV-6. Finally, addition of IL-15 to PBMC cultures was found to severely curtail HHV-6 expression. Taken together, our data suggest that enhanced NK activity in response to viral infection represent a natural anti-viral defense mechanism aimed at rapidly eliminating virus-infected cells.

Full Text

The Full Text of this article is available as a PDF (338.8 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Ablashi D. V., Josephs S. F., Buchbinder A., Hellman K., Nakamura S., Llana T., Lusso P., Kaplan M., Dahlberg J., Memon S. Human B-lymphotropic virus (human herpesvirus-6). J Virol Methods. 1988 Sep;21(1-4):29–48. doi: 10.1016/0166-0934(88)90050-x. [DOI] [PubMed] [Google Scholar]
  2. Bamford R. N., Grant A. J., Burton J. D., Peters C., Kurys G., Goldman C. K., Brennan J., Roessler E., Waldmann T. A. The interleukin (IL) 2 receptor beta chain is shared by IL-2 and a cytokine, provisionally designated IL-T, that stimulates T-cell proliferation and the induction of lymphokine-activated killer cells. Proc Natl Acad Sci U S A. 1994 May 24;91(11):4940–4944. doi: 10.1073/pnas.91.11.4940. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Biron C. A., Byron K. S., Sullivan J. L. Severe herpesvirus infections in an adolescent without natural killer cells. N Engl J Med. 1989 Jun 29;320(26):1731–1735. doi: 10.1056/NEJM198906293202605. [DOI] [PubMed] [Google Scholar]
  4. Burton J. D., Bamford R. N., Peters C., Grant A. J., Kurys G., Goldman C. K., Brennan J., Roessler E., Waldmann T. A. A lymphokine, provisionally designated interleukin T and produced by a human adult T-cell leukemia line, stimulates T-cell proliferation and the induction of lymphokine-activated killer cells. Proc Natl Acad Sci U S A. 1994 May 24;91(11):4935–4939. doi: 10.1073/pnas.91.11.4935. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Ensoli B., Lusso P., Schachter F., Josephs S. F., Rappaport J., Negro F., Gallo R. C., Wong-Staal F. Human herpes virus-6 increases HIV-1 expression in co-infected T cells via nuclear factors binding to the HIV-1 enhancer. EMBO J. 1989 Oct;8(10):3019–3027. doi: 10.1002/j.1460-2075.1989.tb08452.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Flamand L., Gosselin J., D'Addario M., Hiscott J., Ablashi D. V., Gallo R. C., Menezes J. Human herpesvirus 6 induces interleukin-1 beta and tumor necrosis factor alpha, but not interleukin-6, in peripheral blood mononuclear cell cultures. J Virol. 1991 Sep;65(9):5105–5110. doi: 10.1128/jvi.65.9.5105-5110.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Flamand L., Gosselin J., Stefanescu I., Ablashi D., Menezes J. Immunosuppressive effect of human herpesvirus 6 on T-cell functions: suppression of interleukin-2 synthesis and cell proliferation. Blood. 1995 Mar 1;85(5):1263–1271. [PubMed] [Google Scholar]
  8. Flamand L., Stefanescu I., Ablashi D. V., Menezes J. Activation of the Epstein-Barr virus replicative cycle by human herpesvirus 6. J Virol. 1993 Nov;67(11):6768–6777. doi: 10.1128/jvi.67.11.6768-6777.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Fleisher G., Starr S., Koven N., Kamiya H., Douglas S. D., Henle W. A non-x-linked syndrome with susceptibility to severe Epstein-Barr virus infections. J Pediatr. 1982 May;100(5):727–730. doi: 10.1016/s0022-3476(82)80572-6. [DOI] [PubMed] [Google Scholar]
  10. Frenkel N., Schirmer E. C., Katsafanas G., June C. H. T-cell activation is required for efficient replication of human herpesvirus 6. J Virol. 1990 Sep;64(9):4598–4602. doi: 10.1128/jvi.64.9.4598-4602.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Giri J. G., Ahdieh M., Eisenman J., Shanebeck K., Grabstein K., Kumaki S., Namen A., Park L. S., Cosman D., Anderson D. Utilization of the beta and gamma chains of the IL-2 receptor by the novel cytokine IL-15. EMBO J. 1994 Jun 15;13(12):2822–2830. doi: 10.1002/j.1460-2075.1994.tb06576.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Grabstein K. H., Eisenman J., Shanebeck K., Rauch C., Srinivasan S., Fung V., Beers C., Richardson J., Schoenborn M. A., Ahdieh M. Cloning of a T cell growth factor that interacts with the beta chain of the interleukin-2 receptor. Science. 1994 May 13;264(5161):965–968. doi: 10.1126/science.8178155. [DOI] [PubMed] [Google Scholar]
  13. Herberman R. B., Ortaldo J. R. Natural killer cells: their roles in defenses against disease. Science. 1981 Oct 2;214(4516):24–30. doi: 10.1126/science.7025208. [DOI] [PubMed] [Google Scholar]
  14. Horvat R. T., Parmely M. J., Chandran B. Human herpesvirus 6 inhibits the proliferative responses of human peripheral blood mononuclear cells. J Infect Dis. 1993 Jun;167(6):1274–1280. doi: 10.1093/infdis/167.6.1274. [DOI] [PubMed] [Google Scholar]
  15. 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]
  16. Horvat R. T., Wood C., Josephs S. F., Balachandran N. Transactivation of the human immunodeficiency virus promoter by human herpesvirus 6 (HHV-6) strains GS and Z-29 in primary human T lymphocytes and identification of transactivating HHV-6(GS) gene fragments. J Virol. 1991 Jun;65(6):2895–2902. doi: 10.1128/jvi.65.6.2895-2902.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Josephs S. F., Salahuddin S. Z., Ablashi D. V., Schachter F., Wong-Staal F., Gallo R. C. Genomic analysis of the human B-lymphotropic virus (HBLV). Science. 1986 Oct 31;234(4776):601–603. doi: 10.1126/science.3020691. [DOI] [PubMed] [Google Scholar]
  18. Kondo K., Kondo T., Okuno T., Takahashi M., Yamanishi K. Latent human herpesvirus 6 infection of human monocytes/macrophages. J Gen Virol. 1991 Jun;72(Pt 6):1401–1408. doi: 10.1099/0022-1317-72-6-1401. [DOI] [PubMed] [Google Scholar]
  19. Lusso P., De Maria A., Malnati M., Lori F., DeRocco S. E., Baseler M., Gallo R. C. Induction of CD4 and susceptibility to HIV-1 infection in human CD8+ T lymphocytes by human herpesvirus 6. Nature. 1991 Feb 7;349(6309):533–535. doi: 10.1038/349533a0. [DOI] [PubMed] [Google Scholar]
  20. 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]
  21. Lusso P., Malnati M. S., Garzino-Demo A., Crowley R. W., Long E. O., Gallo R. C. Infection of natural killer cells by human herpesvirus 6. Nature. 1993 Apr 1;362(6419):458–462. doi: 10.1038/362458a0. [DOI] [PubMed] [Google Scholar]
  22. Lusso P., Malnati M., De Maria A., Balotta C., DeRocco S. E., Markham P. D., Gallo R. C. Productive infection of CD4+ and CD8+ mature human T cell populations and clones by human herpesvirus 6. Transcriptional down-regulation of CD3. J Immunol. 1991 Jul 15;147(2):685–691. [PubMed] [Google Scholar]
  23. Malnati M. S., Lusso P., Ciccone E., Moretta A., Moretta L., Long E. O. Recognition of virus-infected cells by natural killer cell clones is controlled by polymorphic target cell elements. J Exp Med. 1993 Sep 1;178(3):961–969. doi: 10.1084/jem.178.3.961. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. 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]
  25. Takahashi K., Segal E., Kondo T., Mukai T., Moriyama M., Takahashi M., Yamanishi K. Interferon and natural killer cell activity in patients with exanthem subitum. Pediatr Infect Dis J. 1992 May;11(5):369–373. doi: 10.1097/00006454-199205000-00006. [DOI] [PubMed] [Google Scholar]
  26. Trinchieri G. Biology of natural killer cells. Adv Immunol. 1989;47:187–376. doi: 10.1016/S0065-2776(08)60664-1. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES