Skip to main content
PMC home page
Journal of Virology logoLink to Journal of Virology
. 1997 May;71(5):4016–4023. doi: 10.1128/jvi.71.5.4016-4023.1997

Animal model of mucosally transmitted human immunodeficiency virus type 1 disease: intravaginal and oral deposition of simian/human immunodeficiency virus in macaques results in systemic infection, elimination of CD4+ T cells, and AIDS.

S V Joag 1, I Adany 1, Z Li 1, L Foresman 1, D M Pinson 1, C Wang 1, E B Stephens 1, R Raghavan 1, O Narayan 1
PMCID: PMC191554  PMID: 9094679

Abstract

Chimeric simian/human immunodeficiency virus (SHIV) consists of the env, vpu, tat, and rev genes of human immunodeficiency virus type 1 (HIV-1) on a background of simian immunodeficiency virus (SIV). We derived a SHIV that caused CD4+ cell loss and AIDS in pig-tailed macaques (S. V. Joag, Z. Li, L. Foresman, E. B. Stephens, L. J. Zhao, I. Adany, D. M. Pinson, H. M. McClure, and O. Narayan, J. Virol. 70:3189-3197, 1996) and used a cell-free stock of this virus (SHIV(KU-1)) to inoculate macaques by the intravaginal route. Macaques developed high virus burdens and severe loss of CD4+ cells within 1 month, even when inoculated with only a single animal infectious dose of the virus by the intravaginal route. The infection was characterized by a burst of virus replication that peaked during the first week following intravenous inoculation and a week later in the intravaginally inoculated animals. Intravaginally inoculated animals died within 6 months, with CD4+ counts of <30/microl in peripheral blood, anemia, weight loss, and opportunistic infections (malaria, toxoplasmosis, cryptosporidiosis, and Pneumocystis carinii pneumonia). To evaluate the kinetics of virus spread, we inoculated macaques intravaginally and euthanized them after 2, 4, 7, and 15 days postinoculation. In situ hybridization and immunocytochemistry revealed cells expressing viral RNA and protein in the vagina, uterus, and pelvic and mesenteric lymph nodes in the macaque euthanized on day 2. By day 4, virus-infected cells had disseminated to the spleen and thymus, and by day 15, global elimination of CD4+ T cells was in full progress. Kinetics of viral replication and CD4+ loss were similar in an animal inoculated with pathogenic SHIV orally. This provides a sexual-transmission model of human AIDS that can be used to study the pathogenesis of mucosal infection and to evaluate the efficacy of vaccines and drugs directed against HIV-1.

Full Text

The Full Text of this article is available as a PDF (852.6 KB).

Selected References

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

  1. Baba T. W., Trichel A. M., An L., Liska V., Martin L. N., Murphey-Corb M., Ruprecht R. M. Infection and AIDS in adult macaques after nontraumatic oral exposure to cell-free SIV. Science. 1996 Jun 7;272(5267):1486–1489. doi: 10.1126/science.272.5267.1486. [DOI] [PubMed] [Google Scholar]
  2. Belshe R. B., Graham B. S., Keefer M. C., Gorse G. J., Wright P., Dolin R., Matthews T., Weinhold K., Bolognesi D. P., Sposto R. Neutralizing antibodies to HIV-1 in seronegative volunteers immunized with recombinant gp120 from the MN strain of HIV-1. NIAID AIDS Vaccine Clinical Trials Network. JAMA. 1994 Aug 10;272(6):475–480. doi: 10.1001/jama.272.6.475. [DOI] [PubMed] [Google Scholar]
  3. Egan M. A., Pavlat W. A., Tartaglia J., Paoletti E., Weinhold K. J., Clements M. L., Siliciano R. F. Induction of human immunodeficiency virus type 1 (HIV-1)-specific cytolytic T lymphocyte responses in seronegative adults by a nonreplicating, host-range-restricted canarypox vector (ALVAC) carrying the HIV-1MN env gene. J Infect Dis. 1995 Jun;171(6):1623–1627. doi: 10.1093/infdis/171.6.1623. [DOI] [PubMed] [Google Scholar]
  4. Frankel S. S., Wenig B. M., Burke A. P., Mannan P., Thompson L. D., Abbondanzo S. L., Nelson A. M., Pope M., Steinman R. M. Replication of HIV-1 in dendritic cell-derived syncytia at the mucosal surface of the adenoid. Science. 1996 Apr 5;272(5258):115–117. doi: 10.1126/science.272.5258.115. [DOI] [PubMed] [Google Scholar]
  5. Gorse G. J., Schwartz D. H., Graham B. S., Matthews T. J., Stablein D. M., Frey S. E., Belshe R. B., Clements M. L., Wright P. F., Eibl M. HIV-1 recombinant gp160 vaccine given in accelerated dose schedules. NIAID AIDS Vaccine Clinical Trials Network. Clin Exp Immunol. 1994 Nov;98(2):178–184. doi: 10.1111/j.1365-2249.1994.tb06122.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Igarashi T., Shibata R., Hasebe F., Ami Y., Shinohara K., Komatsu T., Stahl-Hennig C., Petry H., Hunsmann G., Kuwata T. Persistent infection with SIVmac chimeric virus having tat, rev, vpu, env and nef of HIV type 1 in macaque monkeys. AIDS Res Hum Retroviruses. 1994 Aug;10(8):1021–1029. doi: 10.1089/aid.1994.10.1021. [DOI] [PubMed] [Google Scholar]
  7. Joag S. V., Adams R. J., Foresman L., Galbreath D., Zink M. C., Pinson D. M., McClure H., Narayan O. Early activation of PBMC and appearance of antiviral CD8+ cells influence the prognosis of SIV-induced disease in rhesus macaques. J Med Primatol. 1994 Feb-May;23(2-3):108–116. doi: 10.1111/j.1600-0684.1994.tb00110.x. [DOI] [PubMed] [Google Scholar]
  8. Joag S. V., Adams R. J., Pinson D. M., Adany I., Narayan O. Intracerebral infusion of TNF-alpha and IL-6 failed to activate latent SIV infection in the brains of macaques inoculated with macrophage-tropic neuroadapted SIVmac. J Leukoc Biol. 1994 Sep;56(3):353–357. doi: 10.1002/jlb.56.3.353. [DOI] [PubMed] [Google Scholar]
  9. Joag S. V., Li Z., Foresman L., Stephens E. B., Zhao L. J., Adany I., Pinson D. M., McClure H. M., Narayan O. Chimeric simian/human immunodeficiency virus that causes progressive loss of CD4+ T cells and AIDS in pig-tailed macaques. J Virol. 1996 May;70(5):3189–3197. doi: 10.1128/jvi.70.5.3189-3197.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Joag S. V., Stephens E. B., Adams R. J., Foresman L., Narayan O. Pathogenesis of SIVmac infection in Chinese and Indian rhesus macaques: effects of splenectomy on virus burden. Virology. 1994 May 1;200(2):436–446. doi: 10.1006/viro.1994.1207. [DOI] [PubMed] [Google Scholar]
  11. 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]
  12. Miller C. J., Alexander N. J., Vogel P., Anderson J., Marx P. A. Mechanism of genital transmission of SIV: a hypothesis based on transmission studies and the location of SIV in the genital tract of chronically infected female rhesus macaques. J Med Primatol. 1992 Feb-May;21(2-3):64–68. [PubMed] [Google Scholar]
  13. Miller C. J., Vogel P., Alexander N. J., Sutjipto S., Hendrickx A. G., Marx P. A. Localization of SIV in the genital tract of chronically infected female rhesus macaques. Am J Pathol. 1992 Sep;141(3):655–660. [PMC free article] [PubMed] [Google Scholar]
  14. Regier D. A., Desrosiers R. C. The complete nucleotide sequence of a pathogenic molecular clone of simian immunodeficiency virus. AIDS Res Hum Retroviruses. 1990 Nov;6(11):1221–1231. doi: 10.1089/aid.1990.6.1221. [DOI] [PubMed] [Google Scholar]
  15. 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]
  16. Sasseville V. G., Newman W. A., Lackner A. A., Smith M. O., Lausen N. C., Beall D., Ringler D. J. Elevated vascular cell adhesion molecule-1 in AIDS encephalitis induced by simian immunodeficiency virus. Am J Pathol. 1992 Nov;141(5):1021–1030. [PMC free article] [PubMed] [Google Scholar]
  17. Sastry K. J., Nehete P. N., Venkatnarayanan S., Morkowski J., Platsoucas C. D., Arlinghaus R. B. Rapid in vivo induction of HIV-specific CD8+ cytotoxic T lymphocytes by a 15-amino acid unmodified free peptide from the immunodominant V3-loop of GP120. Virology. 1992 Jun;188(2):502–509. doi: 10.1016/0042-6822(92)90504-i. [DOI] [PubMed] [Google Scholar]
  18. Shibata R., Adachi A. SIV/HIV recombinants and their use in studying biological properties. AIDS Res Hum Retroviruses. 1992 Mar;8(3):403–409. doi: 10.1089/aid.1992.8.403. [DOI] [PubMed] [Google Scholar]
  19. 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]
  20. Spira A. I., Marx P. A., Patterson B. K., Mahoney J., Koup R. A., Wolinsky S. M., Ho D. D. Cellular targets of infection and route of viral dissemination after an intravaginal inoculation of simian immunodeficiency virus into rhesus macaques. J Exp Med. 1996 Jan 1;183(1):215–225. doi: 10.1084/jem.183.1.215. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Van de Perre P. Postnatal transmission of human immunodeficiency virus type 1: the breast-feeding dilemma. Am J Obstet Gynecol. 1995 Aug;173(2):483–487. doi: 10.1016/0002-9378(95)90270-8. [DOI] [PubMed] [Google Scholar]
  22. Wang C. Y., Looney D. J., Li M. L., Walfield A. M., Ye J., Hosein B., Tam J. P., Wong-Staal F. Long-term high-titer neutralizing activity induced by octameric synthetic HIV-1 antigen. Science. 1991 Oct 11;254(5029):285–288. doi: 10.1126/science.254.5029.285. [DOI] [PubMed] [Google Scholar]

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

RESOURCES