scholarly journals Advances in Humanized Mouse Models to Improve Understanding of HIV-1 Pathogenesis and Immune Responses

2021 ◽  
Vol 11 ◽  
Author(s):  
Amy Gillgrass ◽  
Jocelyn M. Wessels ◽  
Jack X. Yang ◽  
Charu Kaushic
Keyword(s):  
Mouse Models ◽  
Immune Cells ◽  
Cost Effective ◽  
Viral Reservoir ◽  
Humanized Mouse ◽  
Immunodeficient Mice ◽  
Hiv Management ◽  
Hiv Research ◽  
Advance Research ◽  
Hiv 1

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.

scholarly journals Novel humanized-PBMC mouse model with delayed onset of GVHD for preclinical HIV research

2021 ◽  
Author(s):  
Leo Holguin ◽  
Liliana Echavarria ◽  
John C. Burnetta
Keyword(s):  
Mouse Model ◽  
Mouse Models ◽  
Graft Versus Host Disease ◽  
Clinical Signs ◽  
Humanized Mouse ◽  
Graft Versus Host ◽  
Delayed Onset ◽  
Hiv Research ◽  
Humanized Mouse Models ◽  
Hiv 1

Humanized mouse models are based on the engraftment of human cells in immunodeficient mouse strains, most notably the NSG strain. Most used models have a major limitation in common, the development of graft-versus-host disease (GVHD). GVHD not only introduces variabilities into the research data but also leads to animal welfare concerns. A new mouse strain, B6.129S-Rag2 tm1Fwa CD47 tm1Fpl Il2rg tm1Wjl /J which lacks Rag1, IL2rg, and CD47 (triple knockout or TKO), is resistant to GVHD development. We transplanted TKO mice with human peripheral blood mononuclear cells (PBMCs) to establish a new humanized PBMC (hu-PBMC) mouse model. A cohort of these mice was infected with HIV-1 and monitored for plasma HIV viremia and CD4 + T cell depletion. The onset and progression of GVHD were monitored by clinical signs. This study demonstrates that TKO mice transplanted with human PBMCs support engraftment of human immune cells in primary and secondary lymphoid tissues, rectum, and brain. Moreover, the TKO hu-PBMC model supports HIV-1 infection via intraperitoneal, rectal, or vaginal routes, as confirmed by robust plasma HIV viremia and CD4 + T cell depletion. Lastly, TKO mice showed a delayed onset of GVHD clinical signs (∼28 days) and exhibited significant decreases in plasma levels of TNFβ. Based on these results, the TKO hu-PBMC mouse model not only supports humanization and HIV-1 infection but also has a delayed onset of GVHD development, making this model a valuable tool in HIV research. Importance Currently, there is no cure or vaccine for HIV infection, thus continued research is needed to end the HIV pandemic. While many animal models are used in HIV research, none is used more than the humanized mouse model. A major limitation with current humanized mouse models is the development of graft-versus-host disease (GVHD). Here, we show a novel humanized-PBMC mouse model that has a delayed onset GVHD development and supports and models HIV infection comparable to well-established humanized mouse models.

Humanized Mouse Models of HIV-1 Latency

2011 ◽  
Vol 9 (8) ◽  
pp. 595-605 ◽  
Author(s):  
Rachel V. Duyne ◽  
Aarthi Narayanan ◽  
Kylene K.-Hall ◽  
Mohammed Saifuddin ◽  
Leonard Shultz ◽  
...  
Keyword(s):  
Mouse Models ◽  
Humanized Mouse ◽  
Humanized Mouse Models ◽  
Hiv 1

scholarly journals Modelling of human herpesvirus infections in humanized mice

2014 ◽  
Vol 95 (10) ◽  
pp. 2106-2117 ◽  
Author(s):  
Bradford K. Berges ◽  
Anne Tanner
Keyword(s):  
Mouse Models ◽  
Immune Cells ◽  
Human Herpesvirus ◽  
Antiviral Drugs ◽  
Humanized Mice ◽  
Great Promise ◽  
Humanized Mouse ◽  
Herpes Simplex Viruses ◽  
Human Immune ◽  
Humanized Mouse Models

The human herpesviruses (HHVs) are remarkably successful human pathogens, with some members of the family successfully establishing infection in the vast majority of humans worldwide. Although many HHV infections result in asymptomatic infection or mild disease, there are rare cases of severe disease and death found with nearly every HHV. Many of the pathogenic mechanisms of these viruses are poorly understood, and in many cases, effective antiviral drugs are lacking. Only a single vaccine exists for the HHVs and researchers have been unable to develop treatments to cure the persistent infections associated with HHVs. A major hindrance to HHV research has been the lack of suitable animal models, with the notable exception of the herpes simplex viruses. One promising area for HHV research is the use of humanized mouse models, in which human cells or tissues are transplanted into immunodeficient mice. Current humanized mouse models mostly transplant human haematopoietic stem cells (HSCs), resulting in the production of a variety of human immune cells. Although all HHVs are thought to infect human immune cells, the beta- and gammaherpesviruses extensively infect and establish latency in these cells. Thus, mice humanized with HSCs hold great promise to study these herpesviruses. In this review, we provide a historical perspective on the use of both older and newer humanized mouse models to study HHV infections. The focus is on current developments in using humanized mice to study mechanisms of HHV-induced pathogenesis, human immune responses to HHVs and effectiveness of antiviral drugs.

High-Throughput Humanized Mouse Models for Evaluation of HIV-1 Therapeutics and Pathogenesis

2016 ◽  
pp. 221-235 ◽  
Author(s):  
Tynisha Thomas ◽  
Kieran Seay ◽  
Jian Hua Zheng ◽  
Cong Zhang ◽  
Christina Ochsenbauer ◽  
...  
Keyword(s):  
Mouse Models ◽  
High Throughput ◽  
Humanized Mouse ◽  
Humanized Mouse Models ◽  
Hiv 1

Potential Applications and Perspectives of Humanized Mouse Models

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Weijian Ye ◽  
Qingfeng Chen
Keyword(s):  
Mouse Models ◽  
Biological System ◽  
Disease Modeling ◽  
Annual Review ◽  
Publication Date ◽  
Human Immune System ◽  
Humanized Mouse ◽  
Immunodeficient Mice ◽  
Humanized Mouse Models ◽  
Critical Components

As medical and pharmacological technology advances, new and complex modalities of disease treatment that are more personalized and targeted are being developed. Often these modalities must be validated in the presence of critical components of the human biological system. Given the incongruencies between murine and human biology, as well as the human-tropism of certain drugs and pathogens, the selection of animal models that accurately recapitulate the intricacies of the human biological system becomes more salient for disease modeling and preclinical testing. Immunodeficient mice engrafted with functional human tissues (so-called humanized mice), which allow for the study of physiologically relevant disease mechanisms, have thus become an integral aspect of biomedical research. This review discusses the recent advancements and applications of humanized mouse models on human immune system and liver humanization in modeling human diseases, as well as how they can facilitate translational medicine. Expected final online publication date for the Annual Review of Animal Biosciences, Volume 10 is February 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

scholarly journals Recent Updates on Mouse Models for Human Immunodeficiency, Influenza, and Dengue Viral Infections

Viruses ◽  
2019 ◽  
Vol 11 (3) ◽  
pp. 252 ◽  
Author(s):  
Vinodhini Krishnakumar ◽  
Siva Durairajan ◽  
Kalichamy Alagarasu ◽  
Min Li ◽  
Aditya Dash
Keyword(s):  
Mouse Models ◽  
Viral Infections ◽  
Antiviral Agents ◽  
Immunological Response ◽  
Innate Immune ◽  
Humanized Mouse ◽  
Species Barrier ◽  
Knock Out ◽  
Immunodeficient Mice ◽  
Humanized Mouse Models

Well-developed mouse models are important for understanding the pathogenesis and progression of immunological response to viral infections in humans. Moreover, to test vaccines, anti-viral drugs and therapeutic agents, mouse models are fundamental for preclinical investigations. Human viruses, however, seldom infect mice due to differences in the cellular receptors used by the viruses for entry, as well as in the innate immune responses in mice and humans. In other words, a species barrier exists when using mouse models for investigating human viral infections. Developing transgenic (Tg) mice models expressing the human genes coding for viral entry receptors and knock-out (KO) mice models devoid of components involved in the innate immune response have, to some extent, overcome this barrier. Humanized mouse models are a third approach, developed by engrafting functional human cells and tissues into immunodeficient mice. They are becoming indispensable for analyzing human viral diseases since they nearly recapitulate the human disease. These mouse models also serve to test the efficacy of vaccines and antiviral agents. This review provides an update on the Tg, KO, and humanized mouse models that are used in studies investigating the pathogenesis of three important human-specific viruses, namely human immunodeficiency (HIV) virus 1, influenza, and dengue.

scholarly journals Current humanized mouse models for studying human immunology and HIV-1 immuno-pathogenesis

2010 ◽  
Vol 53 (2) ◽  
pp. 195-203 ◽  
Author(s):  
LiGuo Zhang ◽  
Eric Meissner ◽  
JianZhu Chen ◽  
LiShan Su
Keyword(s):  
Mouse Models ◽  
Humanized Mouse ◽  
Human Immunology ◽  
Humanized Mouse Models ◽  
Hiv 1

scholarly journals Inducible HIV-1 Reservoir Quantification: Clinical Relevance, Applications and Advancements of TILDA

2021 ◽  
Vol 12 ◽  
Author(s):  
Cynthia Lungu ◽  
Riddhima Banga ◽  
Rob A. Gruters ◽  
Francesco A. Procopio
Keyword(s):  
Gold Standard ◽  
Clinical Relevance ◽  
Cost Effective ◽  
Viral Reservoir ◽  
Dilution Assay ◽  
Latent Hiv ◽  
Essential Prerequisite ◽  
Hiv 1 ◽  
Limiting Dilution ◽  
Viral Outgrowth Assay

The presence of a stable HIV-1 reservoir persisting over time despite effective antiretroviral suppression therapy precludes a cure for HIV-1. Characterizing and quantifying this residual reservoir is considered an essential prerequisite to develop and validate curative strategies. However, a sensitive, reproducible, cost-effective, and easily executable test is still needed. The quantitative viral outgrowth assay is considered the gold standard approach to quantify the reservoir in HIV-1-infected patients on suppressive ART, but it has several limitations. An alternative method to quantify the viral reservoir following the reactivation of latent HIV-1 provirus detects multiply-spliced tat/rev RNA (msRNA) molecules by real-time PCR [tat/rev induced limiting dilution assay (TILDA)]. This article provides a perspective overview of the clinical relevance, various applications, recent advancements of TILDA, and how the assay has contributed to our understanding of the HIV-1 reservoir.

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