Skip to main content
PMC home page
Journal of Virology logoLink to Journal of Virology
. 1995 Apr;69(4):2031–2037. doi: 10.1128/jvi.69.4.2031-2037.1995

Molecular and biological analyses of quasispecies during evolution of a virulent simian immunodeficiency virus, SIVsmmPBj14.

B Tao 1, P N Fultz 1
PMCID: PMC188868  PMID: 7884848

Abstract

A prototypic simian immunodeficiency virus (SIVsmm9), isolated from a naturally infected sooty mangabey (Cercocebus atys), was passaged in vivo in a pig-tailed macaque (Macaca nemestrina) having the identifier PBj. When PBj died of a typical AIDS-like syndrome 14 months after infection, the virus isolated from its tissues was subsequently shown to differ from SIVsmm9 genetically and biologically. Most notably, this isolate, SIVsmmPBj14 (SIV-PBj14), is the most virulent primate lentivirus known: it induces acute disease and death within 6 to 10 days after intravenous inoculation into pig-tailed macaques. Between the time of infection with SIVsmm9 and isolation of SIV-PBj14, isolates were obtained periodically from peripheral blood mononuclear cells of PBj. To establish the temporal relationship between evolution of new biologic properties and fixation of specific mutations in the virus population, these sequential SIV-PBj isolates were characterized for unique properties of SIV-PBj14 that appeared to correlate with acute lethal disease. These properties included the ability to replicate in quiescent macaque peripheral blood mononuclear cells, to activate and induce proliferation of CD4+ and CD8+ cells, and to exhibit cytopathicity for mangabey CD4+ lymphocytes. Consistent with earlier studies, a major change in biologic properties occurred between 6 (SIV-PBj6) and 10 (SIV-PBj10) months, with the SIV-PBj8 quasispecies exhibiting properties of both earlier and later isolates. Multiple biologic clones derived from the 6-, 8-, and 10-month isolates also exhibited diverse phenotypes. For example, one SIV-PBj10 biologic clone resembled SIVsmm9 phenotypically, whereas three other biologic clones resembled SIV-PBj14. To evaluate genetic changes, proviral DNA of the biologic clones generated from SIV-PBj6, -PBj8, and -PBj10 was amplified by PCR in the U3 enhancer portion of the long terminal repeats (LTR) and the V1 region of env, where the greatest nucleotide diversity between SIVsmm9 and SIV-PBj14 resided. Nucleotide sequence data indicated that all biologically cloned viruses are distinct and that insertions/duplications of 3 to 27 nucleotides (in multiples of three) had accumulated stepwise in the env V1 region, beginning with SIV-PBj8. In addition, one of four SIV-PBj8 biologic clones had a 22-bp duplication in the LTR which is characteristic of SIV-PBj14. When virus mixtures containing different proportions of two SIV-PBj10 biologic clones with opposite phenotypes were tested, the SIV-PBj14 phenotype was clearly dominant, since mixtures with as few as 10% of the viruses being SIV-PBj14-like exhibited all the properties of the lethal isolate.(ABSTRACT TRUNCATED AT 400 WORDS)

Full Text

The Full Text of this article is available as a PDF (255.3 KB).

Selected References

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

  1. Almond N., Jenkins A., Heath A. B., Kitchin P. Sequence variation in the env gene of simian immunodeficiency virus recovered from immunized macaques is predominantly in the V1 region. J Gen Virol. 1993 May;74(Pt 5):865–871. doi: 10.1099/0022-1317-74-5-865. [DOI] [PubMed] [Google Scholar]
  2. Baier M., Dittmar M. T., Cichutek K., Kurth R. Development of vivo of genetic variability of simian immunodeficiency virus. Proc Natl Acad Sci U S A. 1991 Sep 15;88(18):8126–8130. doi: 10.1073/pnas.88.18.8126. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Burns D. P., Collignon C., Desrosiers R. C. Simian immunodeficiency virus mutants resistant to serum neutralization arise during persistent infection of rhesus monkeys. J Virol. 1993 Jul;67(7):4104–4113. doi: 10.1128/jvi.67.7.4104-4113.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Burns D. P., Desrosiers R. C. Selection of genetic variants of simian immunodeficiency virus in persistently infected rhesus monkeys. J Virol. 1991 Apr;65(4):1843–1854. doi: 10.1128/jvi.65.4.1843-1854.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Campbell B. J., Hirsch V. M. Extensive envelope heterogeneity of simian immunodeficiency virus in tissues from infected macaques. J Virol. 1994 May;68(5):3129–3137. doi: 10.1128/jvi.68.5.3129-3137.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Chackerian B., Morton W. R., Overbaugh J. Persistence of simian immunodeficiency virus Mne variants upon transmission. J Virol. 1994 Jun;68(6):4080–4085. doi: 10.1128/jvi.68.6.4080-4085.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Cheng-Mayer C., Seto D., Tateno M., Levy J. A. Biologic features of HIV-1 that correlate with virulence in the host. Science. 1988 Apr 1;240(4848):80–82. doi: 10.1126/science.2832945. [DOI] [PubMed] [Google Scholar]
  8. Connor R. I., Ho D. D. Human immunodeficiency virus type 1 variants with increased replicative capacity develop during the asymptomatic stage before disease progression. J Virol. 1994 Jul;68(7):4400–4408. doi: 10.1128/jvi.68.7.4400-4408.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Connor R. I., Mohri H., Cao Y., Ho D. D. Increased viral burden and cytopathicity correlate temporally with CD4+ T-lymphocyte decline and clinical progression in human immunodeficiency virus type 1-infected individuals. J Virol. 1993 Apr;67(4):1772–1777. doi: 10.1128/jvi.67.4.1772-1777.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Connor R. I., Notermans D. W., Mohri H., Cao Y., Ho D. D. Biological cloning of functionally diverse quasispecies of HIV-1. AIDS Res Hum Retroviruses. 1993 Jun;9(6):541–546. doi: 10.1089/aid.1993.9.541. [DOI] [PubMed] [Google Scholar]
  11. Courgnaud V., Lauré F., Fultz P. N., Montagnier L., Bréchot C., Sonigo P. Genetic differences accounting for evolution and pathogenicity of simian immunodeficiency virus from a sooty mangabey monkey after cross-species transmission to a pig-tailed macaque. J Virol. 1992 Jan;66(1):414–419. doi: 10.1128/jvi.66.1.414-419.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. 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]
  13. Dewhurst S., Embretson J. E., Fultz P. N., Mullins J. I. Molecular clones from a non-acutely pathogenic derivative of SIVsmmPBj14: characterization and comparison to acutely pathogenic clones. AIDS Res Hum Retroviruses. 1992 Jun;8(6):1179–1187. doi: 10.1089/aid.1992.8.1179. [DOI] [PubMed] [Google Scholar]
  14. 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]
  15. Erickson A. L., Walker C. M. An epitope in the V1 domain of the simian immunodeficiency virus (SIV) gp120 protein is recognized by CD8+ cytotoxic T lymphocytes from an SIV-infected rhesus macaque. J Virol. 1994 Apr;68(4):2756–2759. doi: 10.1128/jvi.68.4.2756-2759.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Fenyö E. M., Morfeldt-Månson L., Chiodi F., Lind B., von Gegerfelt A., Albert J., Olausson E., Asjö B. Distinct replicative and cytopathic characteristics of human immunodeficiency virus isolates. J Virol. 1988 Nov;62(11):4414–4419. doi: 10.1128/jvi.62.11.4414-4419.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Fultz P. N., Anderson D. C., McClure H. M., Dewhurst S., Mullins J. I. SIVsmm infection of macaque and mangabey monkeys: correlation between in vivo and in vitro properties of different isolates. Dev Biol Stand. 1990;72:253–258. [PubMed] [Google Scholar]
  18. Fultz P. N., McClure H. M., Anderson D. C., Swenson R. B., Anand R., Srinivasan A. Isolation of a T-lymphotropic retrovirus from naturally infected sooty mangabey monkeys (Cercocebus atys). Proc Natl Acad Sci U S A. 1986 Jul;83(14):5286–5290. doi: 10.1073/pnas.83.14.5286. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. 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]
  20. 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]
  21. Fultz P. N., Stricker R. B., McClure H. M., Anderson D. C., Switzer W. M., Horaist C. Humoral response to SIV/SMM infection in macaque and mangabey monkeys. J Acquir Immune Defic Syndr. 1990;3(4):319–329. [PubMed] [Google Scholar]
  22. Goodenow M., Huet T., Saurin W., Kwok S., Sninsky J., Wain-Hobson S. HIV-1 isolates are rapidly evolving quasispecies: evidence for viral mixtures and preferred nucleotide substitutions. J Acquir Immune Defic Syndr. 1989;2(4):344–352. [PubMed] [Google Scholar]
  23. Groenink M., Fouchier R. A., de Goede R. E., de Wolf F., Gruters R. A., Cuypers H. T., Huisman H. G., Tersmette M. Phenotypic heterogeneity in a panel of infectious molecular human immunodeficiency virus type 1 clones derived from a single individual. J Virol. 1991 Apr;65(4):1968–1975. doi: 10.1128/jvi.65.4.1968-1975.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Javaherian K., Langlois A. J., Schmidt S., Kaufmann M., Cates N., Langedijk J. P., Meloen R. H., Desrosiers R. C., Burns D. P., Bolognesi D. P. The principal neutralization determinant of simian immunodeficiency virus differs from that of human immunodeficiency virus type 1. Proc Natl Acad Sci U S A. 1992 Feb 15;89(4):1418–1422. doi: 10.1073/pnas.89.4.1418. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Johnson P. R., Hamm T. E., Goldstein S., Kitov S., Hirsch V. M. The genetic fate of molecularly cloned simian immunodeficiency virus in experimentally infected macaques. Virology. 1991 Nov;185(1):217–228. doi: 10.1016/0042-6822(91)90769-8. [DOI] [PubMed] [Google Scholar]
  26. Kodama T., Mori K., Kawahara T., Ringler D. J., Desrosiers R. C. Analysis of simian immunodeficiency virus sequence variation in tissues of rhesus macaques with simian AIDS. J Virol. 1993 Nov;67(11):6522–6534. doi: 10.1128/jvi.67.11.6522-6534.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. 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]
  28. Lori F., Hall L., Lusso P., Popovic M., Markham P., Franchini G., Reitz M. S., Jr Effect of reciprocal complementation of two defective human immunodeficiency virus type 1 (HIV-1) molecular clones on HIV-1 cell tropism and virulence. J Virol. 1992 Sep;66(9):5553–5560. doi: 10.1128/jvi.66.9.5553-5560.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. 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]
  30. Novembre F. J., Hirsch V. M., McClure H. M., Johnson P. R. Molecular diversity of SIVsmm/PBj and a cognate variant, SIVsmm/PGg. J Med Primatol. 1991 Jun;20(4):188–192. [PubMed] [Google Scholar]
  31. Novembre F. J., Johnson P. R., Lewis M. G., Anderson D. C., Klumpp S., McClure H. M., Hirsch V. M. Multiple viral determinants contribute to pathogenicity of the acutely lethal simian immunodeficiency virus SIVsmmPBj variant. J Virol. 1993 May;67(5):2466–2474. doi: 10.1128/jvi.67.5.2466-2474.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Overbaugh J., Rudensey L. M. Alterations in potential sites for glycosylation predominate during evolution of the simian immunodeficiency virus envelope gene in macaques. J Virol. 1992 Oct;66(10):5937–5948. doi: 10.1128/jvi.66.10.5937-5948.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Overbaugh J., Rudensey L. M., Papenhausen M. D., Benveniste R. E., Morton W. R. Variation in simian immunodeficiency virus env is confined to V1 and V4 during progression to simian AIDS. J Virol. 1991 Dec;65(12):7025–7031. doi: 10.1128/jvi.65.12.7025-7031.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Polacino P. S., Liang H. A., Firpo E. J., Clark E. A. T-cell activation influences initial DNA synthesis of simian immunodeficiency virus in resting T lymphocytes from macaques. J Virol. 1993 Dec;67(12):7008–7016. doi: 10.1128/jvi.67.12.7008-7016.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Richman D. D., Bozzette S. A. The impact of the syncytium-inducing phenotype of human immunodeficiency virus on disease progression. J Infect Dis. 1994 May;169(5):968–974. doi: 10.1093/infdis/169.5.968. [DOI] [PubMed] [Google Scholar]
  36. Roos M. T., Lange J. M., de Goede R. E., Coutinho R. A., Schellekens P. T., Miedema F., Tersmette M. Viral phenotype and immune response in primary human immunodeficiency virus type 1 infection. J Infect Dis. 1992 Mar;165(3):427–432. doi: 10.1093/infdis/165.3.427. [DOI] [PubMed] [Google Scholar]
  37. Saag M. S., Hahn B. H., Gibbons J., Li Y., Parks E. S., Parks W. P., Shaw G. M. Extensive variation of human immunodeficiency virus type-1 in vivo. Nature. 1988 Aug 4;334(6181):440–444. doi: 10.1038/334440a0. [DOI] [PubMed] [Google Scholar]
  38. Sakai K., Dewhurst S., Ma X. Y., Volsky D. J. Differences in cytopathogenicity and host cell range among infectious molecular clones of human immunodeficiency virus type 1 simultaneously isolated from an individual. J Virol. 1988 Nov;62(11):4078–4085. doi: 10.1128/jvi.62.11.4078-4085.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Schuitemaker H., Koot M., Kootstra N. A., Dercksen M. W., de Goede R. E., van Steenwijk R. P., Lange J. M., Schattenkerk J. K., Miedema F., Tersmette M. Biological phenotype of human immunodeficiency virus type 1 clones at different stages of infection: progression of disease is associated with a shift from monocytotropic to T-cell-tropic virus population. J Virol. 1992 Mar;66(3):1354–1360. doi: 10.1128/jvi.66.3.1354-1360.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Schwiebert R., Fultz P. N. Immune activation and viral burden in acute disease induced by simian immunodeficiency virus SIVsmmPBj14: correlation between in vitro and in vivo events. J Virol. 1994 Sep;68(9):5538–5547. doi: 10.1128/jvi.68.9.5538-5547.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. 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]
  42. Tan W., Fredriksson R., Björndal A., Balfe P., Fenyö E. M. Cotransfection of HIV-1 molecular clones with restricted cell tropism may yield progeny virus with altered phenotype. AIDS Res Hum Retroviruses. 1993 Apr;9(4):321–329. doi: 10.1089/aid.1993.9.321. [DOI] [PubMed] [Google Scholar]
  43. Tersmette M., Gruters R. A., de Wolf F., de Goede R. E., Lange J. M., Schellekens P. T., Goudsmit J., Huisman H. G., Miedema F. Evidence for a role of virulent human immunodeficiency virus (HIV) variants in the pathogenesis of acquired immunodeficiency syndrome: studies on sequential HIV isolates. J Virol. 1989 May;63(5):2118–2125. doi: 10.1128/jvi.63.5.2118-2125.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Tersmette M., de Goede R. E., Al B. J., Winkel I. N., Gruters R. A., Cuypers H. T., Huisman H. G., Miedema F. Differential syncytium-inducing capacity of human immunodeficiency virus isolates: frequent detection of syncytium-inducing isolates in patients with acquired immunodeficiency syndrome (AIDS) and AIDS-related complex. J Virol. 1988 Jun;62(6):2026–2032. doi: 10.1128/jvi.62.6.2026-2032.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. 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]
  46. el-Farrash M. A., Masuda T., Harada S. Synergistic infectivity of highly and minimally infectious clones of human immunodeficiency virus in vitro. J Infect Dis. 1990 May;161(5):1010–1013. doi: 10.1093/infdis/161.5.1010. [DOI] [PubMed] [Google Scholar]

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

RESOURCES