Abstract
Humanized bone marrow-liver-thymus (HuBLT) mice are a revolutionary small-animal model that has facilitated the study of human immune function and human-restricted pathogens, including human immunodeficiency virus type 1 (HIV-1). These mice recapitulate many aspects of acute and chronic HIV-1 infection, but exhibit weak and variable T-cell responses when challenged with HIV-1, hindering our ability to confidently detect HIV-1–specific responses or vaccine effects. To identify the cause of this, we comprehensively analyzed T-cell development, diversity, and function in HuBLT mice. We found that virtually all HuBLT were well-reconstituted with T cells and had intact TCRβ sequence diversity, thymic development, and differentiation to memory and effector cells. However, there was poor CD4+ and CD8+ T-cell responsiveness to physiologic stimuli and decreased TH1 polarization that correlated with deficient reconstitution of innate immune cells, in particular monocytes. HIV-1 infection of HuBLT mice showed that mice with higher monocyte reconstitution exhibited greater CD8+ T cells responses and HIV-1 viral evolution within predicted HLA-restricted epitopes. Thus, T-cell responses to immune challenges are blunted in HuBLT mice due to a deficiency of innate immune cells, and future efforts to improve the model for HIV-1 immune response and vaccine studies need to be aimed at restoring innate immune reconstitution.
Highlights
Human immunodeficiency virus type 1 (HIV-1) first arose in Africa as a cross-species transmission event of simian immunodeficiency virus (SIV) in the 1930s [1]
We found that while T-cell development and diversity is intact in Humanized bone marrow-liver-thymus (HuBLT) mice, there is a defect in T-cell function and responses to HIV-1 infection that correlates strongly with limited innate immune reconstitution
In order to draw a link between innate immune reconstitution and pathogen-targeted immune responses, we evaluated the effect of monocyte reconstitution on HIV-1 sequence diversity within predicted HLA-restricted epitopes as a metric of CD8+ T
Summary
Human immunodeficiency virus type 1 (HIV-1) first arose in Africa as a cross-species transmission event of simian immunodeficiency virus (SIV) in the 1930s [1]. Non-human primates are a species of close phylogenetic relationship with humans that provide an opportunity to study infections with analogous viruses that closely mimic HIV-1 infection in humans, namely, SIV and recombinant SHIV [reviewed in [3, 4]]. This has allowed for in-depth investigations into pathophysiology of disease and interventional studies. Non-human primate studies are expensive, are complicated by host genetic diversity, and examine the pathogenesis of SIV/SHIV strains, which are different viruses from HIV-1. The most widely studied for HIV-1 is humanized mice, known as “human immune system” (HIS) mice
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