A humanized mouse model for vaginal HIV-1 transmission.

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Abstract Animal models such as small non-human primates and humanized immune system mice (humanized mice) are valuable tools to study HIV prevention by antiretroviral drugs or vaccines. The human bone marrow-liver-thymus (BLT) mouse model allows reconstitution of human lymphoid cells in gut and female reproductive tract (FRT), which makes humanized BLT mice suitable for the studies of HIV mucosal transmission and pre-exposure prophylaxis. To generate humanized BLT mice, human fetal liver and thymus tissue are implanted under the kidney capsule of aforementioned immunodeficient mice engrafted with autologous human HSPCs. The major limitations of the BLT model are: 1) it requires fetal derived human cells and tissues; 2) it develops graft-versus-host disease. Therefore, it is important to develop humanized mouse models that utilize non-fetal derived human HSPCs to reconstitute mucosal human immune system and are susceptible to mucosal HIV transmission. We have developed humanized mouse models that reconstituted human lymphocytes and myeloid cells in the female reproductive tract (FRT), which allowed robust HIV-1 infection through vaginal exposure. Using this mouse model, we propose to investigate: 1) Propagation and dissemination of infection after vaginal exposure to HIV-1; 2) mucosal viral reservoirs in mice treated with antiretroviral drugs; 3) Viral-specific CD8+ T cells in the FRT of HIV-infected mice. Our proposed study will develop a non-fetal derived humanized mouse model that allows robust reconstitution of mucosal human immune cells in the FRT to support vaginal HIV-1 transmission. In addition, it will help us gain a better insight into the human immune responses in the FRT, which will provide implications to the T-cell based vaccine development.