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

Okuma, Kazu
Tanaka, Reiko
Ogura, Tomoyuki
Ito, Mamoru
Kumakura, Sei
Yanaka, Mikiro
Nishizawa, Masako
Sugiura, Wataru
Yamamoto, Naoki
Tanaka, Yuetsu

¹ Department of Immunology, Graduate School and Faculty of Medicine, University of the Ryukyus, Okinawa
² Central Institute for Experimental Animals, Kanagawa
³ Kureha Corporation, Tokyo, Japan
⁴ National Institute of Infectious Diseases, Tokyo, Japan

Potential conflicts of interest: none reported.

Presented in part: First International Workshop on Humanized Mice, Tokyo, 11-12 October 2006 (abstract P-15); 14th Conference on Retroviruses and Opportunistic Infections, Los Angeles, 25-28 February 2007 (abstract 496).

Financial support: Health and Labor Science Research Grant (Research on Publicly Essential Drugs and Medical Devices) from the Ministry of Health, Labor, and Welfare of Japan (grant H16-soyaku-004).

Financial support: National Institutes of Health (grants HL072837 and HL083461 to A.M. and grant HL072117 to L.H.); University-wide AIDS Research Program (grants ID03- SF-027 and ID04-SF-026 to L.H.).

Reprints or correspondence: Dr. Kazu Okuma, Dept. of Immunology, Graduate School and Faculty of Medicine, University of the Ryukyus, Uehara 207, Nishiharacho, Nakagami-gun, Okinawa 903-0215, Japan ([email protected]).

Received 1 May 2007; accepted 11 July 2007

Journal of Infectious Diseases 197(1):p 134-141, January 1, 2008. | 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-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.