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

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

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