Abstract
Although antiretroviral therapy has transformed human immunodeficiency virus-type 1 (HIV-1) from a deadly infection into a chronic disease, it does not clear the viral reservoir, leaving HIV-1 as an uncurable infection. Currently, 1.2 million new HIV-1 infections occur globally each year, with little decrease over many years. Therefore, additional research is required to advance the current state of HIV management, find potential therapeutic strategies, and further understand the mechanisms of HIV pathogenesis and prevention strategies. Non-human primates (NHP) have been used extensively in HIV research and have provided critical advances within the field, but there are several issues that limit their use. Humanized mouse (Hu-mouse) models, or immunodeficient mice engrafted with human immune cells and/or tissues, provide a cost-effective and practical approach to create models for HIV research. Hu-mice closely parallel multiple aspects of human HIV infection and disease progression. Here, we highlight how innovations in Hu-mouse models have advanced HIV-1 research in the past decade. We discuss the effect of different background strains of mice, of modifications on the reconstitution of the immune cells, and the pros and cons of different human cells and/or tissue engraftment methods, on the ability to examine HIV-1 infection and immune response. Finally, we consider the newest advances in the Hu-mouse models and their potential to advance research in emerging areas of mucosal infections, understand the role of microbiota and the complex issues in HIV-TB co-infection. These innovations in Hu-mouse models hold the potential to significantly enhance mechanistic research to develop novel strategies for HIV prevention and therapeutics.
Highlights
Approximately 38 million people are living with human immunodeficiency virus-type 1 (HIV-1), the underlying cause of acquired immune deficiency syndrome (AIDS) [1]
We demonstrated that the frequency of circulating human CD45 + cells was the primary determinant of successful HIV-1 infection following intravaginal exposure in hematopoietic stem cells (HSCs)-engrafted NRG mice
Comparisons between NRG-A2, DRAG, and DRAGA models engrafted with human leukocyte antigen (HLA)-matched HSCs demonstrated that both huDRAG and hu-DRAGA models had significantly better human T-cell reconstitution, CD4/CD8+ T cell function, and most importantly, significant B cell Ig class-switching when compared to NRG-A2 mice [35] and even the hu-bone marrow liver thymus (BLT) models [136] (Table 1)
Summary
Approximately 38 million people are living with human immunodeficiency virus-type 1 (HIV-1), the underlying cause of acquired immune deficiency syndrome (AIDS) [1]. It has been demonstrated that hu-NSG mice successfully reconstitute human CCR5+ CD4+ T cells within the female reproductive tract (FRT) [29, 30], to date, HSC-engrafted NSG mice have not been utilized widely to study mucosal and sexual transmission of HIV-1 [30]. HSC-engrafted NRG mice demonstrated successful mucosal HIV-1 challenge with viral dissemination throughout the FRT and lymphoid tissues [64, 65].
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