Skip to main content
PMC home page
Journal of Virology logoLink to Journal of Virology
. 1996 Jun;70(6):4157–4161. doi: 10.1128/jvi.70.6.4157-4161.1996

Requirements for lymphocyte activation by unusual strains of simian immunodeficiency virus.

Z Du 1, P O Ilyinskii 1, V G Sasseville 1, M Newstein 1, A A Lackner 1, R C Desrosiers 1
PMCID: PMC190308  PMID: 8648760

Abstract

When residues 17 and 18 in nef of simian immunodeficiency virus strain SIVmac239 were changed from RQ to YE, the resultant virus was able to replicate in peripheral blood mononuclear cell cultures without prior lymphocyte activation and without the addition of exogenous interleukin-2, caused extensive lymphocyte activation in these cultures, and produced an acute disease in rhesus and pigtail macaques (Z. Du, S. M. Lang, V. G. Sasseville, A. A. Lackner, P. 0. Ilyinskii, M. D. Daniel, J. U. Jung, and R. C. Desrosiers, Cell 82:665-674, 1995). These properties are similar to those of the acutely lethal pathogen SIVpbj14 but dissimilar to those of the parental SIVmac239. We show here that the single change of R to Y at position 17 in nef of SIVmac239 is sufficient to confer the full, unusual phenotype. Conversely, the lymphocyte-activating properties of SIVpbj14 were lost by the single change of Y to R at position 17 of nef. The change of R17F or Q18E in SIVmac239 nef did not confer the unusual in vitro properties. Since SIVpbj14 has a duplication of the NF-kappaB binding sequence in the transcriptional control region, we also constructed and tested strains of SIVmac239/Rl7Y with zero, one, and two NF-kappaB binding elements. We found no difference in the properties of SIVmac239/R17Y, either in cell culture or in vivo, whether zero, one, or two NF-kappaB binding sites were present. Thus, tyrosine at position 17 of nef is absolutely necessary for the unusual phenotype of SIVpbj14 and is sufficient to convert SIVmac239 to a virus with a phenotype like that of SIVpbjl4. Multiple NF-kappaB binding sites are not required for the in vitro properties or for acute disease.

Full Text

The Full Text of this article is available as a PDF (417.0 KB).

Selected References

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

  1. Cambier J. C. Antigen and Fc receptor signaling. The awesome power of the immunoreceptor tyrosine-based activation motif (ITAM). J Immunol. 1995 Oct 1;155(7):3281–3285. [PubMed] [Google Scholar]
  2. Dewhurst S., Embretson J. E., Anderson D. C., Mullins J. I., Fultz P. N. Sequence analysis and acute pathogenicity of molecularly cloned SIVSMM-PBj14. Nature. 1990 Jun 14;345(6276):636–640. doi: 10.1038/345636a0. [DOI] [PubMed] [Google Scholar]
  3. Dittmar M. T., Cichutek K., Fultz P. N., Kurth R. The U3 promoter region of the acutely lethal simian immunodeficiency virus clone smmPBj1.9 confers related biological activity on the apathogenic clone agm3mc. Proc Natl Acad Sci U S A. 1995 Feb 28;92(5):1362–1366. doi: 10.1073/pnas.92.5.1362. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Dollard S. C., Gummuluru S., Tsang S., Fultz P. N., Dewhurst S. Enhanced responsiveness to nuclear factor kappa B contributes to the unique phenotype of simian immunodeficiency virus variant SIVsmmPBj14. J Virol. 1994 Dec;68(12):7800–7809. doi: 10.1128/jvi.68.12.7800-7809.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Du Z., Lang S. M., Sasseville V. G., Lackner A. A., Ilyinskii P. O., Daniel M. D., Jung J. U., Desrosiers R. C. Identification of a nef allele that causes lymphocyte activation and acute disease in macaque monkeys. Cell. 1995 Aug 25;82(4):665–674. doi: 10.1016/0092-8674(95)90038-1. [DOI] [PubMed] [Google Scholar]
  6. Du Z., Regier D. A., Desrosiers R. C. Improved recombinant PCR mutagenesis procedure that uses alkaline-denatured plasmid template. Biotechniques. 1995 Mar;18(3):376–378. [PubMed] [Google Scholar]
  7. Fultz P. N., McClure H. M., Anderson D. C., Switzer W. M. Identification and biologic characterization of an acutely lethal variant of simian immunodeficiency virus from sooty mangabeys (SIV/SMM). AIDS Res Hum Retroviruses. 1989 Aug;5(4):397–409. doi: 10.1089/aid.1989.5.397. [DOI] [PubMed] [Google Scholar]
  8. Fultz P. N. Replication of an acutely lethal simian immunodeficiency virus activates and induces proliferation of lymphocytes. J Virol. 1991 Sep;65(9):4902–4909. doi: 10.1128/jvi.65.9.4902-4909.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Fultz P. N., Zack P. M. Unique lentivirus--host interactions: SIVsmmPBj14 infection of macaques. Virus Res. 1994 May;32(2):205–225. doi: 10.1016/0168-1702(94)90042-6. [DOI] [PubMed] [Google Scholar]
  10. Gao W. Y., Cara A., Gallo R. C., Lori F. Low levels of deoxynucleotides in peripheral blood lymphocytes: a strategy to inhibit human immunodeficiency virus type 1 replication. Proc Natl Acad Sci U S A. 1993 Oct 1;90(19):8925–8928. doi: 10.1073/pnas.90.19.8925. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Ilyinskii P. O., Desrosiers R. C. Efficient transcription and replication of simian immunodeficiency virus in the absence of NF-kappaB and Sp1 binding elements. J Virol. 1996 May;70(5):3118–3126. doi: 10.1128/jvi.70.5.3118-3126.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Israel Z. R., Dean G. A., Maul D. H., O'Neil S. P., Dreitz M. J., Mullins J. I., Fultz P. N., Hoover E. A. Early pathogenesis of disease caused by SIVsmmPBj14 molecular clone 1.9 in macaques. AIDS Res Hum Retroviruses. 1993 Mar;9(3):277–286. doi: 10.1089/aid.1993.9.277. [DOI] [PubMed] [Google Scholar]
  13. Lewis M. G., Zack P. M., Elkins W. R., Jahrling P. B. Infection of rhesus and cynomolgus macaques with a rapidly fatal SIV (SIVSMM/PBj) isolate from sooty mangabeys. AIDS Res Hum Retroviruses. 1992 Sep;8(9):1631–1639. doi: 10.1089/aid.1992.8.1631. [DOI] [PubMed] [Google Scholar]
  14. 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]
  15. 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]
  16. Pawson T. Protein modules and signalling networks. Nature. 1995 Feb 16;373(6515):573–580. doi: 10.1038/373573a0. [DOI] [PubMed] [Google Scholar]
  17. Reth M. Antigen receptor tail clue. Nature. 1989 Mar 30;338(6214):383–384. doi: 10.1038/338383b0. [DOI] [PubMed] [Google Scholar]
  18. Songyang Z., Shoelson S. E., Chaudhuri M., Gish G., Pawson T., Haser W. G., King F., Roberts T., Ratnofsky S., Lechleider R. J. SH2 domains recognize specific phosphopeptide sequences. Cell. 1993 Mar 12;72(5):767–778. doi: 10.1016/0092-8674(93)90404-e. [DOI] [PubMed] [Google Scholar]
  19. Stevenson M., Stanwick T. L., Dempsey M. P., Lamonica C. A. HIV-1 replication is controlled at the level of T cell activation and proviral integration. EMBO J. 1990 May;9(5):1551–1560. doi: 10.1002/j.1460-2075.1990.tb08274.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Trowbridge I. S., Collawn J. F., Hopkins C. R. Signal-dependent membrane protein trafficking in the endocytic pathway. Annu Rev Cell Biol. 1993;9:129–161. doi: 10.1146/annurev.cb.09.110193.001021. [DOI] [PubMed] [Google Scholar]
  21. Zack J. A., Arrigo S. J., Weitsman S. R., Go A. S., Haislip A., Chen I. S. HIV-1 entry into quiescent primary lymphocytes: molecular analysis reveals a labile, latent viral structure. Cell. 1990 Apr 20;61(2):213–222. doi: 10.1016/0092-8674(90)90802-l. [DOI] [PubMed] [Google Scholar]
  22. 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]

Articles from Journal of Virology are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES