PT - JOURNAL ARTICLE AU - Hannah S. Sperber AU - Padma Priya Togarrati AU - Kyle A. Raymond AU - Mohamed S. Bouzidi AU - Renata Gilfanova AU - Alan G. Gutierrez AU - Marcus O. Muench AU - Satish K. Pillai TI - μ-Lat: A High-Throughput Humanized Mouse Model for Preclinical Evaluation of Human Immunodeficiency Virus Eradication Strategies AID - 10.1101/2020.02.18.955492 DP - 2020 Jan 01 TA - bioRxiv PG - 2020.02.18.955492 4099 - http://biorxiv.org/content/early/2020/02/19/2020.02.18.955492.short 4100 - http://biorxiv.org/content/early/2020/02/19/2020.02.18.955492.full AB - A critical barrier to the development of a human immunodeficiency virus (HIV) cure is the lack of an appropriate and scalable preclinical animal model that enables robust evaluation of candidate eradication approaches prior to testing in humans. Humanized mouse models typically involve engraftment of human fetal tissue and currently face ethical and political challenges. We established a fetal tissue-free humanized model of latent HIV infection, by transplanting “J-Lat” cells, Jurkat cells harboring a latent HIV provirus encoding an enhanced green fluorescent protein (GFP) reporter, into irradiated adult NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice. J-Lat cells exhibited successful engraftment in several tissue sites, including spleen, bone barrow, peripheral blood, and lung, mirroring the diverse tissue tropism of HIV in the human host. Administration of tumor necrosis factor (TNF)-α, an established HIV latency reversal agent, significantly induced GFP expression in engrafted cells across tissues (as measured by flow cytometry at necropsy), reflecting viral reactivation. These data suggest that the “μ-Lat” model enables efficient determination of how effectively viral eradication agents, including latency reversal agents, penetrate and function in diverse anatomical sites harboring HIV in vivo.Importance The search for an HIV cure has been impeded by the lack of convenient and cost-effective preclinical animal models that allow us to evaluate candidate cure approaches prior to testing in humans. In this study, we aim to address this critical gap and present a novel, highly scalable and standardizable HIV-infected humanized mouse model that enables rigorous preclinical testing of HIV cure strategies. In addition to basic safety and tolerability data, the model provides detailed information describing an agent’s therapeutic efficacy as it navigates through tissue-specific barriers and the circulatory, respiratory and excretory systems. Development and dissemination of our humanized mouse platform will help us to move promising HIV cure approaches, including HIV latency reversal and anti-HIV gene therapy strategies, from the laboratory into the clinic.