Interleukin-4-transgenic hu-PBL-SCID mice: a model for the screening of antiviral drugs and immunotherapeutic agents against X4 HIV-1 viruses.
CXCR4-tropic (X4) human immunodeficiency virus type 1 (HIV-1) does not efficiently infect and replicate in severe combined immunodeficiency (SCID) mice reconstituted with human peripheral blood mononuclear cells, termed "hu-PBL-SCID mice," due to, at least in part, relatively low levels of expression of the CXCR4 coreceptor. To overcome this limitation, interleukin (IL)-4-transgenic hu-PBL-SCID mice were derived that spontaneously synthesized human IL-4, which has been shown to enhance CXCR4 expression and promote X4 virus infection in vitro. Experiments reported here show that (1) synthesis of human IL-4 in vivo augmented CXCR4 expression on human CD4(+) lymphocytes and importantly led to productive infection of not only X4 HIV-1(NL4-3) but also multidrug-resistant primary clinical isolates and that (2) the in vivo infection could be significantly blocked by the administration of a CXCR4 antagonist. Altogether, IL-4-transgenic hu-PBL-SCID mice provide a useful model for X4 HIV-1 study and testing/screening of anti-X4 viral drugs.
Okuma
Kazu
K
Department of Immunology, Graduate School and Faculty of Medicine, University of the Ryukyus, Okinawa, Japan. kokuma@med.u-ryukyu.ac.jp
Tanaka
Reiko
R
Ogura
Tomoyuki
T
Ito
Mamoru
M
Kumakura
Sei
S
Yanaka
Mikiro
M
Nishizawa
Masako
M
Sugiura
Wataru
W
Yamamoto
Naoki
N
Tanaka
Yuetsu
Y
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D004195:Disease Models, Animal; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology*; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D015847:Interleukin-4 / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID / Q000235:genetics*; D008822:Mice, Transgenic; D011725:Pyridines / Q000494:pharmacology; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism
C508598:IL4 protein, human; C473941:KRH 1636; D011725:Pyridines; D019718:Receptors, CXCR4; D015847:Interleukin-4; D001120:Arginine