Induction of robust cellular and humoral virus-specific adaptive immune responses in human immunodeficiency virus-infected humanized BLT mice

DM Brainard, E Seung, N Frahm, A Cariappa… - Journal of …, 2009 - Am Soc Microbiol
DM Brainard, E Seung, N Frahm, A Cariappa, CC Bailey, WK Hart, HS Shin, SF Brooks…
Journal of virology, 2009Am Soc Microbiol
The generation of humanized BLT mice by the cotransplantation of human fetal thymus and
liver tissues and CD34+ fetal liver cells into nonobese diabetic/severe combined
immunodeficiency mice allows for the long-term reconstitution of a functional human
immune system, with human T cells, B cells, dendritic cells, and monocytes/macrophages
repopulating mouse tissues. Here, we show that humanized BLT mice sustained high-level
disseminated human immunodeficiency virus (HIV) infection, resulting in CD4+ T-cell …
Abstract
The generation of humanized BLT mice by the cotransplantation of human fetal thymus and liver tissues and CD34+ fetal liver cells into nonobese diabetic/severe combined immunodeficiency mice allows for the long-term reconstitution of a functional human immune system, with human T cells, B cells, dendritic cells, and monocytes/macrophages repopulating mouse tissues. Here, we show that humanized BLT mice sustained high-level disseminated human immunodeficiency virus (HIV) infection, resulting in CD4+ T-cell depletion and generalized immune activation. Following infection, HIV-specific humoral responses were present in all mice by 3 months, and HIV-specific CD4+ and CD8+ T-cell responses were detected in the majority of mice tested after 9 weeks of infection. Despite robust HIV-specific responses, however, viral loads remained elevated in infected BLT mice, raising the possibility that these responses are dysfunctional. The increased T-cell expression of the negative costimulator PD-1 recently has been postulated to contribute to T-cell dysfunction in chronic HIV infection. As seen in human infection, both CD4+ and CD8+ T cells demonstrated increased PD-1 expression in HIV-infected BLT mice, and PD-1 levels in these cells correlated positively with viral load and inversely with CD4+ cell levels. The ability of humanized BLT mice to generate both cellular and humoral immune responses to HIV will allow the further investigation of human HIV-specific immune responses in vivo and suggests that these mice are able to provide a platform to assess candidate HIV vaccines and other immunotherapeutic strategies.
American Society for Microbiology