Skip to main content
NCBI home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1994 Feb 1;179(2):513–522. doi: 10.1084/jem.179.2.513

Disseminated human immunodeficiency virus 1 (HIV-1) infection in SCID- hu mice after peripheral inoculation with HIV-1

PMCID: PMC2191362  PMID: 8294863

Abstract

A small animal model that could be infected with human immunodeficiency virus 1 (HIV-1) after peripheral inoculation would greatly facilitate the study of the pathophysiology of acute HIV-1 infection. The utility of SCID mice implanted with human fetal thymus and liver (SCID-hu mice) for studying peripheral HIV-1 infection in vivo has been hampered by the requirement for direct intraimplant injection of HIV-1 and the continued restriction of the resultant HIV-1 infection to the human thymus and liver (hu-thy/liv) implant. This may have been due to the very low numbers of human T cells present in the SCID-hu mouse peripheral lymphoid compartment. Since the degree of the peripheral reconstitution of SCID-hu mice with human T cells may be a function of the hu-thy/liv implant size, we increased the quantity of hu-thy/liv tissue implanted under the renal capsule and implanted hu-thy/liv tissue under the capsules of both kidneys. This resulted in SCID-hu mice in which significant numbers of human T cells were detected in the peripheral blood, spleens, and lymph nodes. After intraimplant injection of HIV-1 into these modified SCID-hu mice, significant HIV-1 infection was detected by quantitative coculture not only in the hu- thy/liv implant, but also in the spleen and peripheral blood. This indicated that HIV-1 infection can spread from the thymus to the peripheral lymphoid compartment. More importantly, a similar degree of infection of the hu-thy/liv implant and peripheral lymphoid compartment occurred after peripheral intraperitoneal inoculation with HIV-1. Active viral replication was indicated by the detection of HIV-1 gag DNA, HIV-1 gag RNA, and spliced tat/rev RNA in the hu-thy/liv implants, peripheral blood mononuclear cells (PBMC), spleens, and lymph nodes of these HIV-1-infected SCID-hu mice. As a first step in using our modified SCID-hu mouse model to investigate the pathophysiological consequences of HIV-1 infection, the effect of HIV-1 infection on the expression of human cytokines shown to enhance HIV-1 replication was examined. Significantly more of the HIV-1-infected SCID-hu mice expressed mRNA for human tumor necrosis factors alpha and beta, and interleukin 2 in their spleens, lymph nodes, and PBMC than did uninfected SCID-hu mice. This suggested that HIV-1 infection in vivo can stimulate the expression of cytokine mRNA by human T cells.(ABSTRACT TRUNCATED AT 400 WORDS)

Full Text

The Full Text of this article is available as a PDF (1.1 MB).

Selected References

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

  1. Aldrovandi G. M., Feuer G., Gao L., Jamieson B., Kristeva M., Chen I. S., Zack J. A. The SCID-hu mouse as a model for HIV-1 infection. Nature. 1993 Jun 24;363(6431):732–736. doi: 10.1038/363732a0. [DOI] [PubMed] [Google Scholar]
  2. Bonyhadi M. L., Rabin L., Salimi S., Brown D. A., Kosek J., McCune J. M., Kaneshima H. HIV induces thymus depletion in vivo. Nature. 1993 Jun 24;363(6431):728–732. doi: 10.1038/363728a0. [DOI] [PubMed] [Google Scholar]
  3. Buonaguro L., Barillari G., Chang H. K., Bohan C. A., Kao V., Morgan R., Gallo R. C., Ensoli B. Effects of the human immunodeficiency virus type 1 Tat protein on the expression of inflammatory cytokines. J Virol. 1992 Dec;66(12):7159–7167. doi: 10.1128/jvi.66.12.7159-7167.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Courgnaud V., Lauré F., Brossard A., Bignozzi C., Goudeau A., Barin F., Bréchot C. Frequent and early in utero HIV-1 infection. AIDS Res Hum Retroviruses. 1991 Mar;7(3):337–341. doi: 10.1089/aid.1991.7.337. [DOI] [PubMed] [Google Scholar]
  5. De Rossi A., Ometto L., Mammano F., Zanotto C., Giaquinto C., Chieco-Bianchi L. Vertical transmission of HIV-1: lack of detectable virus in peripheral blood cells of infected children at birth. AIDS. 1992 Oct;6(10):1117–1120. [PubMed] [Google Scholar]
  6. Dimitrov D. H., Melnick J. L., Hollinger F. B. Microculture assay for isolation of human immunodeficiency virus type 1 and for titration of infected peripheral blood mononuclear cells. J Clin Microbiol. 1990 Apr;28(4):734–737. doi: 10.1128/jcm.28.4.734-737.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Ehrnst A., Lindgren S., Dictor M., Johansson B., Sönnerborg A., Czajkowski J., Sundin G., Bohlin A. B. HIV in pregnant women and their offspring: evidence for late transmission. Lancet. 1991 Jul 27;338(8761):203–207. doi: 10.1016/0140-6736(91)90347-r. [DOI] [PubMed] [Google Scholar]
  8. Embretson J., Zupancic M., Ribas J. L., Burke A., Racz P., Tenner-Racz K., Haase A. T. Massive covert infection of helper T lymphocytes and macrophages by HIV during the incubation period of AIDS. Nature. 1993 Mar 25;362(6418):359–362. doi: 10.1038/362359a0. [DOI] [PubMed] [Google Scholar]
  9. English B. K., Weaver W. M., Wilson C. B. Differential regulation of lymphotoxin and tumor necrosis factor genes in human T lymphocytes. J Biol Chem. 1991 Apr 15;266(11):7108–7113. [PubMed] [Google Scholar]
  10. Fink P. J., Bevan M. J., Weissman I. L. Thymic cytotoxic T lymphocytes are primed in vivo to minor histocompatibility antigens. J Exp Med. 1984 Feb 1;159(2):436–451. doi: 10.1084/jem.159.2.436. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Hays E. F., Uittenbogaart C. H., Brewer J. C., Vollger L. W., Zack J. A. In vitro studies of HIV-1 expression in thymocytes from infants and children. AIDS. 1992 Mar;6(3):265–272. doi: 10.1097/00002030-199203000-00003. [DOI] [PubMed] [Google Scholar]
  12. Hirano T., Fujimoto K., Teranishi T., Nishino N., Onoue K., Maeda S., Shimada K. Phorbol ester increases the level of interleukin 2 mRNA in mitogen-stimulated human lymphocytes. J Immunol. 1984 May;132(5):2165–2167. [PubMed] [Google Scholar]
  13. Hirokawa K., Utsuyama M., Sado T. Immunohistological analysis of immigration of thymocyte-precursors into the thymus: evidence for immigration of peripheral T cells into the thymic medulla. Cell Immunol. 1989 Mar;119(1):160–170. doi: 10.1016/0008-8749(89)90232-3. [DOI] [PubMed] [Google Scholar]
  14. Ho D. D., Moudgil T., Alam M. Quantitation of human immunodeficiency virus type 1 in the blood of infected persons. N Engl J Med. 1989 Dec 14;321(24):1621–1625. doi: 10.1056/NEJM198912143212401. [DOI] [PubMed] [Google Scholar]
  15. Kollmann T. R., Goldstein M. M., Goldstein H. The concurrent maturation of mouse and human thymocytes in human fetal thymus implanted in NIH-beige-nude-xid mice is associated with the reconstitution of the murine immune system. J Exp Med. 1993 Mar 1;177(3):821–832. doi: 10.1084/jem.177.3.821. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Kollmann T. R., Zhuang X., Rubinstein A., Goldstein H. Design of polymerase chain reaction primers for the selective amplification of HIV-1 RNA in the presence of HIV-1 DNA. AIDS. 1992 Jun;6(6):547–552. doi: 10.1097/00002030-199206000-00004. [DOI] [PubMed] [Google Scholar]
  17. Krivine A., Firtion G., Cao L., Francoual C., Henrion R., Lebon P. HIV replication during the first weeks of life. Lancet. 1992 May 16;339(8803):1187–1189. doi: 10.1016/0140-6736(92)91131-q. [DOI] [PubMed] [Google Scholar]
  18. Krone W. J., Sninsky J. J., Goudsmit J. Detection and characterization of HIV-1 by polymerase chain reaction. J Acquir Immune Defic Syndr. 1990;3(5):517–524. [PubMed] [Google Scholar]
  19. Krowka J. F., Sarin S., Namikawa R., McCune J. M., Kaneshima H. Human T cells in the SCID-hu mouse are phenotypically normal and functionally competent. J Immunol. 1991 Jun 1;146(11):3751–3756. [PubMed] [Google Scholar]
  20. Lindstein T., June C. H., Ledbetter J. A., Stella G., Thompson C. B. Regulation of lymphokine messenger RNA stability by a surface-mediated T cell activation pathway. Science. 1989 Apr 21;244(4902):339–343. doi: 10.1126/science.2540528. [DOI] [PubMed] [Google Scholar]
  21. Mano H., Chermann J. C. Fetal human immunodeficiency virus type 1 infection of different organs in the second trimester. AIDS Res Hum Retroviruses. 1991 Jan;7(1):83–88. doi: 10.1089/aid.1991.7.83. [DOI] [PubMed] [Google Scholar]
  22. McCune J. M. HIV-1: the infective process in vivo. Cell. 1991 Jan 25;64(2):351–363. doi: 10.1016/0092-8674(91)90644-e. [DOI] [PubMed] [Google Scholar]
  23. Namikawa R., Kaneshima H., Lieberman M., Weissman I. L., McCune J. M. Infection of the SCID-hu mouse by HIV-1. Science. 1988 Dec 23;242(4886):1684–1686. doi: 10.1126/science.3201256. [DOI] [PubMed] [Google Scholar]
  24. Namikawa R., Weilbaecher K. N., Kaneshima H., Yee E. J., McCune J. M. Long-term human hematopoiesis in the SCID-hu mouse. J Exp Med. 1990 Oct 1;172(4):1055–1063. doi: 10.1084/jem.172.4.1055. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Naparstek Y., Holoshitz J., Eisenstein S., Reshef T., Rappaport S., Chemke J., Ben-Nun A., Cohen I. R. Effector T lymphocyte line cells migrate to the thymus and persist there. Nature. 1982 Nov 18;300(5889):262–264. doi: 10.1038/300262a0. [DOI] [PubMed] [Google Scholar]
  26. Pantaleo G., Graziosi C., Butini L., Pizzo P. A., Schnittman S. M., Kotler D. P., Fauci A. S. Lymphoid organs function as major reservoirs for human immunodeficiency virus. Proc Natl Acad Sci U S A. 1991 Nov 1;88(21):9838–9842. doi: 10.1073/pnas.88.21.9838. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Pantaleo G., Graziosi C., Demarest J. F., Butini L., Montroni M., Fox C. H., Orenstein J. M., Kotler D. P., Fauci A. S. HIV infection is active and progressive in lymphoid tissue during the clinically latent stage of disease. Nature. 1993 Mar 25;362(6418):355–358. doi: 10.1038/362355a0. [DOI] [PubMed] [Google Scholar]
  28. Pantaleo G., Graziosi C., Fauci A. S. New concepts in the immunopathogenesis of human immunodeficiency virus infection. N Engl J Med. 1993 Feb 4;328(5):327–335. doi: 10.1056/NEJM199302043280508. [DOI] [PubMed] [Google Scholar]
  29. Papiernik M., Brossard Y., Mulliez N., Roume J., Brechot C., Barin F., Goudeau A., Bach J. F., Griscelli C., Henrion R. Thymic abnormalities in fetuses aborted from human immunodeficiency virus type 1 seropositive women. Pediatrics. 1992 Feb;89(2):297–301. [PubMed] [Google Scholar]
  30. Schnittman S. M., Denning S. M., Greenhouse J. J., Justement J. S., Baseler M., Kurtzberg J., Haynes B. F., Fauci A. S. Evidence for susceptibility of intrathymic T-cell precursors and their progeny carrying T-cell antigen receptor phenotypes TCR alpha beta + and TCR gamma delta + to human immunodeficiency virus infection: a mechanism for CD4+ (T4) lymphocyte depletion. Proc Natl Acad Sci U S A. 1990 Oct;87(19):7727–7731. doi: 10.1073/pnas.87.19.7727. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Schnittman S. M., Greenhouse J. J., Lane H. C., Pierce P. F., Fauci A. S. Frequent detection of HIV-1-specific mRNAs in infected individuals suggests ongoing active viral expression in all stages of disease. AIDS Res Hum Retroviruses. 1991 Apr;7(4):361–367. doi: 10.1089/aid.1991.7.361. [DOI] [PubMed] [Google Scholar]
  32. Schnittman S. M., Singer K. H., Greenhouse J. J., Stanley S. K., Whichard L. P., Le P. T., Haynes B. F., Fauci A. S. Thymic microenvironment induces HIV expression. Physiologic secretion of IL-6 by thymic epithelial cells up-regulates virus expression in chronically infected cells. J Immunol. 1991 Oct 15;147(8):2553–2558. [PubMed] [Google Scholar]
  33. Temin H. M., Bolognesi D. P. AIDS. Where has HIV been hiding? Nature. 1993 Mar 25;362(6418):292–293. doi: 10.1038/362292a0. [DOI] [PubMed] [Google Scholar]
  34. Yamamura M., Uyemura K., Deans R. J., Weinberg K., Rea T. H., Bloom B. R., Modlin R. L. Defining protective responses to pathogens: cytokine profiles in leprosy lesions. Science. 1991 Oct 11;254(5029):277–279. doi: 10.1126/science.254.5029.277. [DOI] [PubMed] [Google Scholar]
  35. 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]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press

RESOURCES