Progress toward a human CD4/CCR5 transgenic rat model for de novo infection by human immunodeficiency virus type 1.
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.
Keppler
Oliver T
OT
Gladstone Institute of Virology and Immunology, School of Medicine, University of California at San Francisco, San Francisco, CA 94141, USA.
Welte
Frank J
FJ
Ngo
Tuan A
TA
Chin
Peggy S
PS
Patton
Kathryn S
KS
Tsou
Chia-Lin
CL
Abbey
Nancy W
NW
Sharkey
Mark E
ME
Grant
Robert M
RM
You
Yun
Y
Scarborough
John D
JD
Ellmeier
Wilfried
W
Littman
Dan R
DR
Stevenson
Mario
M
Charo
Israel F
IF
Herndier
Brian G
BG
Speck
Roberto F
RF
Goldsmith
Mark A
MA
D000818:Animals; D030801:Animals, Genetically Modified; D015704:CD4 Antigens / Q000235:genetics / Q000276:immunology; D004195:Disease Models, Animal; D015658:HIV Infections; D015497:HIV-1 / Q000502:physiology; D006801:Humans; D008264:Macrophages / Q000276:immunology; D051381:Rats; D019713:Receptors, CCR5 / Q000235:genetics / Q000276:immunology; D014779:Virus Replication
D015704:CD4 Antigens; D019713:Receptors, CCR5