CD34T+ Humanized Mouse Model to Study Mucosal HIV-1 Transmission and Prevention.

Kanika Vanshylla,Ricarda Stumpf,Christof Geldmacher,Henning Gruell,Tabea M Eser,Jan Münch,Berthold Grüttner,Florian Klein,Kathrin Held,Kanika Jain,Daniela Weiland,Franziska Kleipass

doi:10.3390/vaccines9030198

Abstract

Humanized mice are critical for HIV-1 research, but humanized mice generated from cord blood are inefficient at mucosal HIV-1 transmission. Most mucosal HIV-1 transmission studies in mice require fetal tissue-engraftment, the use of which is highly restricted or prohibited. We present a fetal tissue-independent model called CD34T+ with enhanced human leukocyte levels in the blood and improved T cell homing to the gut-associated lymphoid tissue. CD34T+ mice are highly permissive to intra-rectal HIV-1 infection and also show normal env diversification in vivo despite high viral replication. Moreover, mucosal infection in CD34T+ mice can be prevented by infusion of broadly neutralizing antibodies. CD34T+ mice can be rapidly and easily generated using only cord blood cells and do not require any complicated surgical procedures for the humanization process. Therefore, CD34T+ mice provide a novel platform for mucosal HIV-1 transmission studies as well as rapid in vivo testing of novel prevention molecules against HIV-1.

Highlights

Despite immense progress in the treatment of HIV-1 infection, transmission of the virus continues due to the lack of a vaccine that elicits full protection [1]
Since CD34 mice are a widely used and readily available humanized mouse model [19], we aimed to develop this model for generating mice that can be used for mucosal HIV-1 transmission and prevention
CD34 humanized mice were generated by engraftment with CD34+ hematopoietic stem cells (HSCs) isolated from human umbilical cord blood as follows: 1–5 days old NOD-Rag1null IL2rgnull (NRG) mice were sub-lethally irradiated at a dose of ~2.0 Gy and 4–6 h later injected intra-hepatically with 2 × 105 purified CD34+ HSCs

Summary

Introduction

Despite immense progress in the treatment of HIV-1 infection, transmission of the virus continues due to the lack of a vaccine that elicits full protection [1]. Anti-retroviral pre-exposure prophylaxis (PrEP) has shown efficacy in preventing HIV-1 transmission [2]. The pre-clinical in vivo evaluation of the efficacy of anti-HIV-1 molecules has been mostly limited to nonhuman primates (NHPs) and humanized mice [4,5]. NHPs have a fully functional simian immune system and are susceptible to infection via sexual/mucosal routes making them highly useful for mucosal HIV-1 prevention studies. Experiments with NHPs require the use of recombinant Simian-HIV to successfully infect primate immune cells [4]. Humanized mice harbor human immune cells that can be infected with labadapted or primary isolates of HIV-1 and have been useful in the evaluation of antiviral efficacy of several antiretroviral drugs and monoclonal antibodies [6,7,8]

Objectives

Methods

Results

Conclusion