Limitations of the Human-PBL-SCID Mouse Model for Vaginal Transmission of HIV-1 Osmond J. D’Cruz 1,2 , Fatih M. Uckun 1,2 1 Parker Hughes Institute, St Paul, MN, USA; 2 Paradigm Pharmaceuticals, St Paul, MN, USA Introduction Severe combined immunodeficient mice (SCID) engrafted with human peripheral blood lymphocytes (hu-PBL) represent a useful model in AIDS research, including the preclinical evaluation of cell-associated HIV-1 transmission as well as for screening anti-HIV agents for their potential efficacy in preventing gen- ital transmission of HIV-1. 1–5 Human-SCID mouse model of HIV-1 infection following intraperitoneal inoculation with HIV-1-infected human-PBLs is quite effective as a research tool for studying HIV-1 infection, pathogenesis, and viral fitness. 6,7 HIV-1 infection can be detected in 100% of animals after 2 weeks and the infection persists for up to 16 weeks at several body organs, and rapid loss of CD4 + T cell occurs. 8 Antiretroviral treatment of SCID mice har- boring human-PBL obtained from HIV-infected Keywords HIV/AIDS, human-SCID mice, intravaginal, microbicides, sexual transmission Correspondence Osmond J. D’Cruz, Parker Hughes Institute, 2657 Patton Road, St Paul, MN 55113, USA. E-mail: odcruz@ih.org Submitted December 14, 2006; accepted January 17, 2006. Citation D’Cruz OJ, Uckun FM. Limitations of the Human-PBL-SCID Mouse Model for Vaginal Transmission of HIV-1. Am J Reprod Immunol 2007; 57: 353–360 doi:10.1111/j.1600-0897.2007.00478.x Problem SCID mice reconstituted with human peripheral blood lymphocytes (PBL) are amenable to vaginal transmission of HIV-1. We investigated the effectiveness of this model to establish systemic HIV-1 infection. Method of study Eighty progesterone-primed C.B-17 SCID mice were reconstituted with human-PBLs and intravaginally inoculated with CCR5 HIV-1 (BaL or 92BR09) infected human-PBLs in the presence of human semen. After two weeks, viral RNA load in spleen, peritoneal lavage (PL), and serum was quantitated by the nucleic acid sequence-based amplification method. Results In five independent experiments, spleen from 8/60 (13.3%), PL from 7/ 60 (11.6%), and serum from 16/56 (28.5%) mice were positive for BaL HIV-1 infection. Similarly, spleen from 4/20 (20%), PL from 1/20 (5%) and serum from 5/20 (25%) mice vaginally inoculated with 92BR09- infected human-PBLs were positive for HIV-1. A one-sided power analy- sis using normal approximation revealed that at 5% significance level, the overall response rate need to increase form 0.29 to 0.9 and 80% of the control groups needs to achieve a response rate between 6/10 and 9/10 to make the assay feasible. Conclusion The incidence of vaginal transmission of CCR5 HIV-1 in the human- PBL-SCID mouse was low and variable, which constitutes a major dis- advantage for preclinical evaluation of vaginal microbicides. ORIGINAL ARTICLE American Journal of Reproductive Immunology 57 (2007) 353–360 ª 2007 The Authors Journal compilation ª 2007 Blackwell Munksgaard 353