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. 1995 Nov;69(11):7061–7067. doi: 10.1128/jvi.69.11.7061-7067.1995

Persistent infection of macaques with simian-human immunodeficiency viruses.

J T Li 1, M Halloran 1, C I Lord 1, A Watson 1, J Ranchalis 1, M Fung 1, N L Letvin 1, J G Sodroski 1
PMCID: PMC189626  PMID: 7474126

Abstract

Chimeric simian-human immunodeficiency viruses (SHIV) containing the human immunodeficiency virus type 1 (HIV-1) tat, rev, env, and, in some cases, vpu genes were inoculated into eight cynomolgus monkeys. Viruses could be consistently recovered from the CD8-depleted peripheral blood lymphocytes of all eight animals for at least 2 months. After this time, virus isolation varied among the animals, with viruses continuing to be isolated from some animals beyond 600 days after inoculation. The level of viral RNA in plasma during acute infection and the frequency of virus isolation after the initial 2-month period were higher for the Vpu-positive viruses. All of the animals remained clinically healthy, and the absolute numbers of CD4-positive lymphocytes were stable. Antibodies capable of neutralizing HIV-1 were generated at high titers in animals exhibiting the greatest consistency of virus isolation. Strain-specific HIV-1-neutralizing antibodies were initially elicited, and then more broadly neutralizing antibodies were elicited. env sequences from two viruses isolated more than a year after infection were analyzed. In the Vpu-negative SHIV, for which virus loads were lower, a small amount of env variation, which did not correspond to that found in natural HIV-1 variants, was observed. By contrast, in the Vpu-positive virus, which was consistently isolated from the host animal, extensive variation of the envelope glycoproteins in the defined variable gp120 regions was observed. Escape from neutralization by CD4 binding site monoclonal antibodies was observed for the viruses with the latter envelope glycoproteins, and the mechanism of escape appears to involve decreased binding of the antibody to the monomeric gp120 glycoproteins. The consistency with which SHIV infection of cynomolgus monkeys is initiated and the similarities in the neutralizing antibody response to SHIV and HIV-1 support the utility of this model system for the study of HIV-1 prophylaxis.

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Selected References

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  1. Agy M. B., Frumkin L. R., Corey L., Coombs R. W., Wolinsky S. M., Koehler J., Morton W. R., Katze M. G. Infection of Macaca nemestrina by human immunodeficiency virus type-1. Science. 1992 Jul 3;257(5066):103–106. doi: 10.1126/science.1621083. [DOI] [PubMed] [Google Scholar]
  2. Albert J., Abrahamsson B., Nagy K., Aurelius E., Gaines H., Nyström G., Fenyö E. M. Rapid development of isolate-specific neutralizing antibodies after primary HIV-1 infection and consequent emergence of virus variants which resist neutralization by autologous sera. AIDS. 1990 Feb;4(2):107–112. doi: 10.1097/00002030-199002000-00002. [DOI] [PubMed] [Google Scholar]
  3. Barré-Sinoussi F., Chermann J. C., Rey F., Nugeyre M. T., Chamaret S., Gruest J., Dauguet C., Axler-Blin C., Vézinet-Brun F., Rouzioux C. Isolation of a T-lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS). Science. 1983 May 20;220(4599):868–871. doi: 10.1126/science.6189183. [DOI] [PubMed] [Google Scholar]
  4. 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]
  5. Burton D. R., Pyati J., Koduri R., Sharp S. J., Thornton G. B., Parren P. W., Sawyer L. S., Hendry R. M., Dunlop N., Nara P. L. Efficient neutralization of primary isolates of HIV-1 by a recombinant human monoclonal antibody. Science. 1994 Nov 11;266(5187):1024–1027. doi: 10.1126/science.7973652. [DOI] [PubMed] [Google Scholar]
  6. Choi W. S., Collignon C., Thiriart C., Burns D. P., Stott E. J., Kent K. A., Desrosiers R. C. Effects of natural sequence variation on recognition by monoclonal antibodies neutralize simian immunodeficiency virus infectivity. J Virol. 1994 Sep;68(9):5395–5402. doi: 10.1128/jvi.68.9.5395-5402.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Clavel F., Guétard D., Brun-Vézinet F., Chamaret S., Rey M. A., Santos-Ferreira M. O., Laurent A. G., Dauguet C., Katlama C., Rouzioux C. Isolation of a new human retrovirus from West African patients with AIDS. Science. 1986 Jul 18;233(4761):343–346. doi: 10.1126/science.2425430. [DOI] [PubMed] [Google Scholar]
  8. Collman R., Balliet J. W., Gregory S. A., Friedman H., Kolson D. L., Nathanson N., Srinivasan A. An infectious molecular clone of an unusual macrophage-tropic and highly cytopathic strain of human immunodeficiency virus type 1. J Virol. 1992 Dec;66(12):7517–7521. doi: 10.1128/jvi.66.12.7517-7521.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Dalgleish A. G., Beverley P. C., Clapham P. R., Crawford D. H., Greaves M. F., Weiss R. A. The CD4 (T4) antigen is an essential component of the receptor for the AIDS retrovirus. Nature. 1984 Dec 20;312(5996):763–767. doi: 10.1038/312763a0. [DOI] [PubMed] [Google Scholar]
  10. Desrosiers R. C., Daniel M. D., Li Y. HIV-related lentiviruses of nonhuman primates. AIDS Res Hum Retroviruses. 1989 Oct;5(5):465–473. doi: 10.1089/aid.1989.5.465. [DOI] [PubMed] [Google Scholar]
  11. Desrosiers R. C. The simian immunodeficiency viruses. Annu Rev Immunol. 1990;8:557–578. doi: 10.1146/annurev.iy.08.040190.003013. [DOI] [PubMed] [Google Scholar]
  12. Fauci A. S., Macher A. M., Longo D. L., Lane H. C., Rook A. H., Masur H., Gelmann E. P. NIH conference. Acquired immunodeficiency syndrome: epidemiologic, clinical, immunologic, and therapeutic considerations. Ann Intern Med. 1984 Jan;100(1):92–106. doi: 10.7326/0003-4819-100-1-92. [DOI] [PubMed] [Google Scholar]
  13. Frumkin L. R., Agy M. B., Coombs R. W., Panther L., Morton W. R., Koehler J., Florey M. J., Dragavon J., Schmidt A., Katze M. G. Acute infection of Macaca nemestrina by human immunodeficiency virus type 1. Virology. 1993 Aug;195(2):422–431. doi: 10.1006/viro.1993.1392. [DOI] [PubMed] [Google Scholar]
  14. Fultz P. N., McClure H. M., Daugharty H., Brodie A., McGrath C. R., Swenson B., Francis D. P. Vaginal transmission of human immunodeficiency virus (HIV) to a chimpanzee. J Infect Dis. 1986 Nov;154(5):896–900. doi: 10.1093/infdis/154.5.896. [DOI] [PubMed] [Google Scholar]
  15. Gallo R. C., Salahuddin S. Z., Popovic M., Shearer G. M., Kaplan M., Haynes B. F., Palker T. J., Redfield R., Oleske J., Safai B. Frequent detection and isolation of cytopathic retroviruses (HTLV-III) from patients with AIDS and at risk for AIDS. Science. 1984 May 4;224(4648):500–503. doi: 10.1126/science.6200936. [DOI] [PubMed] [Google Scholar]
  16. Geraghty R. J., Panganiban A. T. Human immunodeficiency virus type 1 Vpu has a CD4- and an envelope glycoprotein-independent function. J Virol. 1993 Jul;67(7):4190–4194. doi: 10.1128/jvi.67.7.4190-4194.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Goudsmit J., Debouck C., Meloen R. H., Smit L., Bakker M., Asher D. M., Wolff A. V., Gibbs C. J., Jr, Gajdusek D. C. Human immunodeficiency virus type 1 neutralization epitope with conserved architecture elicits early type-specific antibodies in experimentally infected chimpanzees. Proc Natl Acad Sci U S A. 1988 Jun;85(12):4478–4482. doi: 10.1073/pnas.85.12.4478. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Goudsmit J., Thiriart C., Smit L., Bruck C., Gibbs C. J. Temporal development of cross-neutralization between HTLV-III B and HTLV-III RF in experimentally infected chimpanzees. Vaccine. 1988 Jun;6(3):229–232. doi: 10.1016/0264-410x(88)90216-2. [DOI] [PubMed] [Google Scholar]
  19. Gurgo C., Guo H. G., Franchini G., Aldovini A., Collalti E., Farrell K., Wong-Staal F., Gallo R. C., Reitz M. S., Jr Envelope sequences of two new United States HIV-1 isolates. Virology. 1988 Jun;164(2):531–536. doi: 10.1016/0042-6822(88)90568-5. [DOI] [PubMed] [Google Scholar]
  20. Göttlinger H. G., Dorfman T., Cohen E. A., Haseltine W. A. Vpu protein of human immunodeficiency virus type 1 enhances the release of capsids produced by gag gene constructs of widely divergent retroviruses. Proc Natl Acad Sci U S A. 1993 Aug 1;90(15):7381–7385. doi: 10.1073/pnas.90.15.7381. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Haseltine W. A. Replication and pathogenesis of the AIDS virus. J Acquir Immune Defic Syndr. 1988;1(3):217–240. [PubMed] [Google Scholar]
  22. 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]
  23. Joag S. V., Anderson M. G., Clements J. E., McEntee M. F., Sharma D. P., Adams R. J., Narayan O. Antigenic variation of molecularly cloned SIVmac239 during persistent infection in a rhesus macaque. Virology. 1993 Aug;195(2):406–412. doi: 10.1006/viro.1993.1390. [DOI] [PubMed] [Google Scholar]
  24. Kestler H. W., 3rd, Ringler D. J., Mori K., Panicali D. L., Sehgal P. K., Daniel M. D., Desrosiers R. C. Importance of the nef gene for maintenance of high virus loads and for development of AIDS. Cell. 1991 May 17;65(4):651–662. doi: 10.1016/0092-8674(91)90097-i. [DOI] [PubMed] [Google Scholar]
  25. Klatzmann D., Champagne E., Chamaret S., Gruest J., Guetard D., Hercend T., Gluckman J. C., Montagnier L. T-lymphocyte T4 molecule behaves as the receptor for human retrovirus LAV. Nature. 1984 Dec 20;312(5996):767–768. doi: 10.1038/312767a0. [DOI] [PubMed] [Google Scholar]
  26. Lang S. M., Weeger M., Stahl-Hennig C., Coulibaly C., Hunsmann G., Müller J., Müller-Hermelink H., Fuchs D., Wachter H., Daniel M. M. Importance of vpr for infection of rhesus monkeys with simian immunodeficiency virus. J Virol. 1993 Feb;67(2):902–912. doi: 10.1128/jvi.67.2.902-912.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Lenburg M. E., Landau N. R. Vpu-induced degradation of CD4: requirement for specific amino acid residues in the cytoplasmic domain of CD4. J Virol. 1993 Dec;67(12):7238–7245. doi: 10.1128/jvi.67.12.7238-7245.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Li J., Lord C. I., Haseltine W., Letvin N. L., Sodroski J. Infection of cynomolgus monkeys with a chimeric HIV-1/SIVmac virus that expresses the HIV-1 envelope glycoproteins. J Acquir Immune Defic Syndr. 1992;5(7):639–646. [PubMed] [Google Scholar]
  29. Moore J. P., McCutchan F. E., Poon S. W., Mascola J., Liu J., Cao Y., Ho D. D. Exploration of antigenic variation in gp120 from clades A through F of human immunodeficiency virus type 1 by using monoclonal antibodies. J Virol. 1994 Dec;68(12):8350–8364. doi: 10.1128/jvi.68.12.8350-8364.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Muesing M. A., Smith D. H., Cabradilla C. D., Benton C. V., Lasky L. A., Capon D. J. Nucleic acid structure and expression of the human AIDS/lymphadenopathy retrovirus. Nature. 1985 Feb 7;313(6002):450–458. doi: 10.1038/313450a0. [DOI] [PubMed] [Google Scholar]
  31. Posner M. R., Hideshima T., Cannon T., Mukherjee M., Mayer K. H., Byrn R. A. An IgG human monoclonal antibody that reacts with HIV-1/GP120, inhibits virus binding to cells, and neutralizes infection. J Immunol. 1991 Jun 15;146(12):4325–4332. [PubMed] [Google Scholar]
  32. Rho H. M., Poiesz B., Ruscetti F. W., Gallo R. C. Characterization of the reverse transcriptase from a new retrovirus (HTLV) produced by a human cutaneous T-cell lymphoma cell line. Virology. 1981 Jul 15;112(1):355–360. doi: 10.1016/0042-6822(81)90642-5. [DOI] [PubMed] [Google Scholar]
  33. Roben P., Moore J. P., Thali M., Sodroski J., Barbas C. F., 3rd, Burton D. R. Recognition properties of a panel of human recombinant Fab fragments to the CD4 binding site of gp120 that show differing abilities to neutralize human immunodeficiency virus type 1. J Virol. 1994 Aug;68(8):4821–4828. doi: 10.1128/jvi.68.8.4821-4828.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Sakuragi S., Shibata R., Mukai R., Komatsu T., Fukasawa M., Sakai H., Sakuragi J., Kawamura M., Ibuki K., Hayami M. Infection of macaque monkeys with a chimeric human and simian immunodeficiency virus. J Gen Virol. 1992 Nov;73(Pt 11):2983–2987. doi: 10.1099/0022-1317-73-11-2983. [DOI] [PubMed] [Google Scholar]
  35. Schwartz S., Felber B. K., Fenyö E. M., Pavlakis G. N. Env and Vpu proteins of human immunodeficiency virus type 1 are produced from multiple bicistronic mRNAs. J Virol. 1990 Nov;64(11):5448–5456. doi: 10.1128/jvi.64.11.5448-5456.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Shibata R., Kawamura M., Sakai H., Hayami M., Ishimoto A., Adachi A. Generation of a chimeric human and simian immunodeficiency virus infectious to monkey peripheral blood mononuclear cells. J Virol. 1991 Jul;65(7):3514–3520. doi: 10.1128/jvi.65.7.3514-3520.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Smith L. M., Sanders J. Z., Kaiser R. J., Hughes P., Dodd C., Connell C. R., Heiner C., Kent S. B., Hood L. E. Fluorescence detection in automated DNA sequence analysis. Nature. 1986 Jun 12;321(6071):674–679. doi: 10.1038/321674a0. [DOI] [PubMed] [Google Scholar]
  38. Sullivan N., Sun Y., Li J., Hofmann W., Sodroski J. Replicative function and neutralization sensitivity of envelope glycoproteins from primary and T-cell line-passaged human immunodeficiency virus type 1 isolates. J Virol. 1995 Jul;69(7):4413–4422. doi: 10.1128/jvi.69.7.4413-4422.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Terwilliger E. F., Cohen E. A., Lu Y. C., Sodroski J. G., Haseltine W. A. Functional role of human immunodeficiency virus type 1 vpu. Proc Natl Acad Sci U S A. 1989 Jul;86(13):5163–5167. doi: 10.1073/pnas.86.13.5163. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Thali M., Olshevsky U., Furman C., Gabuzda D., Posner M., Sodroski J. Characterization of a discontinuous human immunodeficiency virus type 1 gp120 epitope recognized by a broadly reactive neutralizing human monoclonal antibody. J Virol. 1991 Nov;65(11):6188–6193. doi: 10.1128/jvi.65.11.6188-6193.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Von Gegerfelt A., Albert J., Morfeldt-Månson L., Broliden K., Fenyö E. M. Isolate-specific neutralizing antibodies in patients with progressive HIV-1-related disease. Virology. 1991 Nov;185(1):162–168. doi: 10.1016/0042-6822(91)90764-3. [DOI] [PubMed] [Google Scholar]
  42. Willey R. L., Maldarelli F., Martin M. A., Strebel K. Human immunodeficiency virus type 1 Vpu protein induces rapid degradation of CD4. J Virol. 1992 Dec;66(12):7193–7200. doi: 10.1128/jvi.66.12.7193-7200.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Willey R. L., Maldarelli F., Martin M. A., Strebel K. Human immunodeficiency virus type 1 Vpu protein regulates the formation of intracellular gp160-CD4 complexes. J Virol. 1992 Jan;66(1):226–234. doi: 10.1128/jvi.66.1.226-234.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Yao X. J., Göttlinger H., Haseltine W. A., Cohen E. A. Envelope glycoprotein and CD4 independence of vpu-facilitated human immunodeficiency virus type 1 capsid export. J Virol. 1992 Aug;66(8):5119–5126. doi: 10.1128/jvi.66.8.5119-5126.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Zeger S. L., Liang K. Y. Longitudinal data analysis for discrete and continuous outcomes. Biometrics. 1986 Mar;42(1):121–130. [PubMed] [Google Scholar]
  46. Zhang Y. J., Putkonen P., Albert J., Ohman P., Biberfeld G., Fenyö E. M. Stable biological and antigenic characteristics of HIV-2SBL6669 in nonpathogenic infection of macaques. Virology. 1994 May 1;200(2):583–589. doi: 10.1006/viro.1994.1221. [DOI] [PubMed] [Google Scholar]

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