Interleukin-4—Transgenic hu-PBL-SCID Mice: A Model for the Screening of Antiviral Drugs and Immunotherapeutic Agents against X4 HIV-1 Viruses

• Published in: The Journal of infectious diseases 2008-01, Vol.197 (1), p.134-141
• Main Authors: Okuma, Kazu, Tanaka, Reiko, Ogura, Tomoyuki, Ito, Mamoru, Kumakura, Sei, Yanaka, Mikiro, Nishizawa, Masako, Sugiura, Wataru, Yamamoto, Naoki, Tanaka, Yuetsu
• Format: Article
• Language: English
• Subjects: Animals; Arginine - analogs & derivatives; Arginine - pharmacology; Biological and medical sciences; Cytometry; Disease Models, Animal; Fundamental and applied biological sciences. Psychology; HIV 1; HIV Infections - drug therapy; HIV Infections - virology; HIV-1 - drug effects; HIV/AIDS; Human immunodeficiency virus 1; Humans; Infections; Interleukin-4 - genetics; Interleukin-4 - metabolism; Mice; Mice, SCID - genetics; Mice, Transgenic; Microbiology; Miscellaneous; Peritoneal lavage; Pyridines - pharmacology; Receptors; Receptors, CXCR4 - antagonists & inhibitors; Receptors, CXCR4 - genetics; Receptors, CXCR4 - metabolism; T lymphocytes; Transgenic animals; Virology; Viruses
• ISSN: 0022-1899; 1537-6613
• DOI: 10.1086/524303

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-1NL4-3 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.