Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Live attenuated, multiply deleted simian immunodeficiency virus causes AIDS in infant and adult macaques

Nature Medicine volume 5, pages 194–203 (1999)Cite this article

An Erratum to this article was published on 01 May 1999

Abstract

A substantial risk in using live attenuated, multiply deleted viruses as vaccines against AIDS is their potential to induce AIDS. A mutant of the simian immunodeficiency virus (SIV) with large deletions in nef and vpr and in the negative regulatory element induced AIDS in six of eight infant macaques vaccinated orally or intravenously. Early signs of immune dysfunction were seen in the remaining two offspring. Prolonged follow–up of sixteen vaccinated adult macaques also showed resurgence of chronic viremia in four animals: two of these developed early signs of disease and one died of AIDS. We conclude that this multiply deleted SIV is pathogenic and that human AIDS vaccines built on similar prototypes may cause AIDS.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: PCR detection of additional deletions within the 3´ LTR/nef regions of genomic DNA isolated from SIVmac239Δ3–infected animals.
Figure 2: Kaplan–Meier survival curves for infants inoculated orally or intravenously as neonates with SIVmac239Δ3 (solid line) or orally with wild–type SIVmac251 (dotted line).
Figure 3: Western blot analysis of plasma samples obtained from SIVmac239Δ3–infected infant/mother pair (a–c) and adult N141 (d).
Figure 4: In situ hybridization analysis of lymph node sections from infant/mother pair 93–4/A95.

Similar content being viewed by others

References

  1. Letvin, N.L. Vaccines against human immunodeficiency virus – Progress and prospects. N. Engl. J. Med. 329, 1400– 1405 (1993).

    Article  CAS  PubMed  Google Scholar 

  2. Letvin, N.L. & King, N.W. Immunologic and pathologic manifestations of the infection of rhesus monkeys with simian immunodeficiency virus of macaques. J. Acquir. Immune Defic. Syndr. 3, 1023–1040 (1990).

    CAS  PubMed  Google Scholar 

  3. Davison–Fairburn, B. et al. Experimental infection of timed–pregnant rhesus monkeys with simian immunodeficiency virus (SIV) during middle, and late gestation. J. Med. Primatol. 19,381– 393 (1990).

    PubMed  Google Scholar 

  4. Ochs, H.D. et al. Maternal–fetal transmission of SIV in macaques: Disseminated adenovirus infection in an offspring with congenital SIV infection. J. Med. Primatol. 20, 193–200 (1991).

    CAS  PubMed  Google Scholar 

  5. Amedee, A.M. et al. Genotypic selection of simian immunodeficiency virus in macaque infants infected transplacentally. J. Virol. 69, 7982–7990 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Daniel, M.D., Kirchhoff, F., Czajak, S.C., Sehgal, P.K. & Desrosiers, R.C. Protective effects of a live attenuated SIV vaccine with a deletion in the nef gene. Science 258, 1938–1941 (1992).

    Article  CAS  PubMed  Google Scholar 

  7. Whatmore, A.M. et al. Repair and evolution of nef in vivo modulates simian immunodeficiency virus virulence. J. Virol. 69, 5117–5123 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Almond, N. et al. Protection by attenuated simian immunodeficiency virus in macaques against challenge with virus–infected cells. Lancet 345, 1342–1344 (1995).

    Article  CAS  PubMed  Google Scholar 

  9. Norley, S., Beer, B., Binninger–Schninzel, D., Cosma, C. & Kurth, R. Protection from pathogenic SIVmac challenge following short–term infection with a nef–deficient attenuated virus. Virology 219, 195– 205 (1996).

    Article  CAS  PubMed  Google Scholar 

  10. Wyand, M.S., Manson, K.H., Garcia–Moll, M., Montefiori, D. & Desrosiers, R.C. Vaccine protection by a triple deletion mutant of simian immunodeficiency virus. J. Virol. 70, 3724–3733 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Clements, J.E. et al. Cross–protective immune responses induced in rhesus macaques by immunization with attenuated macrophage–tropic simian immunodeficiency virus. J. Virol. 69, 2737– 2744 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Kestler, H.W. 3rd. et al. Importance of the nef gene for maintenance of high virus loads and for development of AIDS. Cell 65, 651–662 (1991).

    Article  CAS  PubMed  Google Scholar 

  13. Gibbs, J.S., Regier, D. A. & Desrosiers, R.C. Construction and in vitro properties of SIVmac mutants with deletions in "nonessential" genes. AIDS Res. Hum. Retroviruses 10, 607–616 (1994).

    Article  CAS  PubMed  Google Scholar 

  14. Baba, T.W. et al. Pathogenicity of live, attenuated SIV after mucosal infection of neonatal macaques. Science 267, 1820– 1825 (1995).

    Article  CAS  PubMed  Google Scholar 

  15. Wyand, M.S., Manson K.H., Lackner, A.A. & Desrosiers, R.C. Resistance of neonatal monkeys to live attenuated vaccine strains of simian immunodeficiency virus. Nature Med. 3, 32–36 (1997).

    Article  CAS  PubMed  Google Scholar 

  16. Liska, V., Lerche, N.W. & Ruprecht, R.M. Simultaneous detection of simian retrovirus type D serotypes 1, 2, and 3 by polymerase chain reaction. AIDS Res. Hum. Retroviruses 13, 433–437 (1997).

    Article  CAS  PubMed  Google Scholar 

  17. Connor, R.I. et al. Temporal analyses of virus replication, immune responses, and efficacy in rhesus macaques immunized with a live, attenuated simian immunodeficiency virus vaccine. J. Virol. 72, 7501– 7509 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Binley, J. M. et al. Differential regulation of the antibody responses to Gag and Env proteins of human immunodeficiency virus type 1. J. Virol. 71, 2799–2809 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Zhang, J.–Y. et al. Simian immunodeficiency virus/Delta–induced disease in rhesus monkeys: Relation of antibody response and antigenemia. J. Infect. Dis. 158, 1277–1286 (1988).

    Article  CAS  PubMed  Google Scholar 

  20. Kindt, T.J., Hirsch, V.M., Johnson, P.R. & Sawasdikosol, S. Animal models for acquired immunodeficiency syndrome. Adv. Immunol. 52, 425–474 (1992).

    Article  CAS  PubMed  Google Scholar 

  21. Pantaleo, G. et al. HIV infection is active and progressive in lymphoid tissue during the clinically latent stage of disease. Nature 362, 355–358 (1993).

    Article  CAS  PubMed  Google Scholar 

  22. Embretson, J. et al. Massive covert infection of helper T lymphocytes and macrophages by HIV during the incubation period of AIDS. Nature 362, 359–362 (1993).

    Article  CAS  PubMed  Google Scholar 

  23. Rosenberg, Y.J. et al. Immunological and virological changes associated with decline in CD4/CD8 ratios in lymphoid organs of SIV–infected macaques. AIDS Res. Hum. Retroviruses 10, 863– 872 (1994).

    Article  CAS  PubMed  Google Scholar 

  24. Baskin G.B. et al. Lentivirus–induced pulmonary lesions in rhesus monkeys (Macaca mulatta) infected with simian immunodeficiency virus. Vet. Pathol. 28, 506–513 (1991).

    Article  CAS  PubMed  Google Scholar 

  25. Kirchoff F., Kestler H.W. III & Desrosiers, R.C. Upstream U3 sequences in simian immunodeficiency virus are selectively deleted in the absence of an intact nef gene. J. Virol. 68, 2031–2037 (1994).

    Google Scholar 

  26. Baba, T.W. et al. Attenuated retrovirus vaccines and AIDS. Science 270, 1220–1222 (1995).

    CAS  Google Scholar 

  27. Ruprecht, R.M., Baba, T.W., Rasmussen, R., Hu, Y. & Sharma, P. L. Murine and simian retrovirus models: The threshold hypothesis. AIDS 10 (suppl A), S33–S40 (1996).

    Article  PubMed  Google Scholar 

  28. Garcia, J.V. & Miller, D. Serine phosphorylation–independent downregulation of cell–surface CD4 by nef. Nature 350, 508–511 (1991).

    Article  CAS  PubMed  Google Scholar 

  29. Aiken, C., Konner, J., Landau, N.R., Lenburg, M.E. & Trono, D. Nef induces CD4 endocytosis: Requirement for a critical dileucine motif in the membrane–proximal CD4 cytoplasmic domain. Cell 76, 853–864 (1994).

    Article  CAS  PubMed  Google Scholar 

  30. Schwartz, O., Marechal, V., Le Gall, S., Lemonnier F. & Heard, J.M. Endocytosis of major histocompatibility complex class I molecules is induced by the HIV–1 Nef protein. Nature Med. 2, 338–342 (1996).

    Article  CAS  PubMed  Google Scholar 

  31. Miller, M.D., Warmerdam, M.T ., Gaston, I., Greene, W.C. & Feinberg, M.B. The human immunodeficiency virus–1 nef gene product: A positive factor for viral infection and replication in primary lymphocytes and macrophages. J. Exp. Med. 179, 101–113 (1994).

    Article  CAS  PubMed  Google Scholar 

  32. Spina, C.A., Kwoh, T.J., Chowers, M.Y., Guatelli, J.C. & Richman, D.D. The importance of nef in the induction of human immunodeficiency virus type 1 replication from primary quiescent CD4 lymphocytes. J. Exp. Med. 179, 115–123 (1994).

    Article  CAS  PubMed  Google Scholar 

  33. Fazely, F., Haseltine, W.A., Rodger, R.F. & Ruprecht, R.M. Simian immunodeficiency virus infection via amniotic fluid: A model to study fetal immunopathogenesis and prophylaxis. J. Acq. Immune Defic. Syndr. 6, 107–114 (1993).

    CAS  Google Scholar 

  34. Desrosiers, R.C. Safety issues facing development of a live–attenuated, multiply deleted HIV–1 vaccine. AIDS Res. Hum. Retroviruses 10, 331–332 (1994).

    Article  CAS  PubMed  Google Scholar 

  35. Sabin, A. B. Oral poliovirus vaccine: History of its development and use and current challenge to eliminate poliomyelitis from the world. J. Infect. Dis. 151, 420–436 (1985).

    Article  CAS  PubMed  Google Scholar 

  36. Liska, V., Fultz, P.N., Su, L. & Ruprecht, R.M. Detection of simian T cell leukemia virus type I infection in seronegative macaques. AIDS Res. Hum. Retroviruses 13, 1147– 1153 (1997).

    Article  CAS  PubMed  Google Scholar 

  37. Baba, T.W. et al. Mucosal infection of neonatal rhesus monkeys with cell–free SIV. AIDS Res. Hum. Retroviruses 10, 351–357 (1994).

    Article  CAS  PubMed  Google Scholar 

  38. Baba T.W. et al. Infection and AIDS in adult macaques after nontraumatic oral exposure to cell–free SIV. Science 272, 1486–1489 (1996).

    Article  CAS  PubMed  Google Scholar 

  39. Tsai, C.–C. et al. Effects of (R)–9–(2–phosphonylmethoxypropyl) adenine monotherapy on chronic SIV infection in macaques. AIDS Res. Hum. Retroviruses 13, 707–712 (1997).

    Article  CAS  PubMed  Google Scholar 

  40. Fox, C.H. & Cottler–Fox, M.H. in Current Protocols in Immunology. (eds. Coligan, J., Kruisbeek, A., Margulies, D., Shevach, E., & Stober, W.)(Wiley, New York, 1993).

    Google Scholar 

  41. Marx, P.A. et al. Progesterone implants enhance SIV vaginal transmission and early virus load. Nature Med. 2, 1084– 1089 (1996).

    Article  CAS  PubMed  Google Scholar 

  42. Centers for Disease Control. 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. Morbid. Mortal. Weekly Rep. 41 (numder RR–17), 1–19 (1992).

    Google Scholar 

Download references

Acknowledgements

We thank J. Andersen (Harvard School of Public Health) for assistance with statistical analyses, R. Desrosiers (New England Regional Primate Research Center) for his contribution of SIVmac239Δ3 virus stock, P. Mack for veterinary care, A. Li for help with western blot analysis, C. Lanclos for technical assistance, and C. Gallegos and S. Sharp for the preparation of this manuscript. Supported in part by NIH grants RO1–AI32330, UO1–AI24345, and RO1–AI35533 to R.M.R. and by the Center for AIDS Research core grant IP30 28691. T.W.B. is a recipient of an NIH Clinical Investigator Development Award (KO8–AI01327). Supported also in part by NIH/NCRR grants RR–00164 and RR–00165 awarded to the Tulane Regional Primate Research Center and to the Yerkes Regional Primate Research Center, respectively.

Author information

Authors and Affiliations

  1. Dana–Farber Cancer Institute, 44 Binney Street, Boston, 02115, Massachusetts, USA

    Timothy W. Baba, Vladimir Liska, Anis H. Khimani, Nancy B. Ray & Ruth M. Ruprecht

  2. Department of Medicine, Harvard Medical School, 25 Shattuck Street, Boston, 02115, Massachusetts, USA

    Timothy W. Baba, Vladimir Liska, Anis H. Khimani, Nancy B. Ray & Ruth M. Ruprecht

  3. Division of Newborn Medicine, Department of Pediatrics, Tufts University School of Medicine, Boston, 02111, Massachusetts, USA

    Timothy W. Baba

  4. Chiron Corporation, Emeryville, 94608, California, USA

    Peter J. Dailey

  5. Department of Radiology, Tufts School of Veterinary Medicine, Grafton, 01536, Massachusetts, USA

    Dominique Penninck

  6. Tufts University School of Veterinary Medicine, Boston, 02111, Massachusetts, USA

    Rod Bronson

  7. Department of Obstetrics and Gynecology, Massachusetts General Hospital, Fruit Street, Boston, 02114, Massachusetts, USA

    Michael F. Greene

  8. Yerkes Regional Primate Research Center, and Department of Pathology, Emory University, Atlanta, 30322, Georgia, USA

    Harold M. McClure

  9. Tulane Regional Primate Research Center, Covington, 70433, Louisiana, USA

    Louis N. Martin

Authors
  1. Timothy W. Baba
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Vladimir Liska
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Anis H. Khimani
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Nancy B. Ray
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Peter J. Dailey
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Dominique Penninck
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Rod Bronson
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Michael F. Greene
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Harold M. McClure
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Louis N. Martin
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Ruth M. Ruprecht
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Baba, T., Liska, V., Khimani, A. et al. Live attenuated, multiply deleted simian immunodeficiency virus causes AIDS in infant and adult macaques. Nat Med 5, 194–203 (1999). https://doi.org/10.1038/5557

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/5557

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing