Progress toward a human CD4/CCR5 transgenic rat model for de novo infection by human immunodeficiency virus type 1

Oliver T. Keppler, Frank J. Welte, Tuan A. Ngo, Peggy S. Chin, Kathryn S. Patton, Chia Lin Tsou, Nancy W. Abbey, Mark E. Sharkey, Robert M. Grant, Yun You, John D. Scarborough, Wilfried Ellmeier, Dan R. Littman, Mario Stevenson, Israel F. Charo, Brian G. Herndier, Roberto F. Speck, Mark A. Goldsmith

Research output: Contribution to journalArticle

82 Scopus citations

Abstract

The development of a permissive small animal model for the study of human immunodeficiency virus type (HIV)-1 pathogenesis and the testing of antiviral strategies has been hampered by the inability of HIV-1 to infect primary rodent cells productively. In this study, we explored transgenic rats expressing the HIV-1 receptor complex as a susceptible host. Rats transgenic for human CD4 (hCD4) and the human chemokine receptor CCR5 (hCCR5) were generated that express the transgenes in CD4+ T lymphocytes, macrophages, and microglia. In ex vivo cultures, CD4+ T lymphocytes, macrophages, and microglia from hCD4/hCCR5 transgenic rats were highly susceptible to infection by HIV-1 R5 viruses leading to expression of abundant levels of early HIV-1 gene products comparable to those found in human reference cultures. Primary rat macrophages and microglia, but not lymphocytes, from double-transgenic rats could be productively infected by various recombinant and primary R5 strains of HIV-1. Moreover, after systemic challenge with HIV-1, lymphatic organs from hCD4/hCCR5 transgenic rats contained episomal 2-long terminal repeat (LTR) circles, integrated provirus, and early viral gene products, demonstrating susceptibility to HIV-1 in vivo. Transgenic rats also displayed a low-level plasma viremia early in infection. Thus, transgenic rats expressing the appropriate human receptor complex are promising candidates for a small animal model of HIV-1 infection.

Original languageEnglish (US)
Pages (from-to)719-736
Number of pages18
JournalJournal of Experimental Medicine
Volume195
Issue number6
DOIs
StatePublished - Mar 18 2002

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Keywords

  • CCR5
  • CD4
  • HIV-1
  • Macrophages
  • Transgenic rats

ASJC Scopus subject areas

  • Immunology

Cite this

Keppler, O. T., Welte, F. J., Ngo, T. A., Chin, P. S., Patton, K. S., Tsou, C. L., Abbey, N. W., Sharkey, M. E., Grant, R. M., You, Y., Scarborough, J. D., Ellmeier, W., Littman, D. R., Stevenson, M., Charo, I. F., Herndier, B. G., Speck, R. F., & Goldsmith, M. A. (2002). Progress toward a human CD4/CCR5 transgenic rat model for de novo infection by human immunodeficiency virus type 1. Journal of Experimental Medicine, 195(6), 719-736. https://doi.org/10.1084/jem.20011549