Improvements and Limitations of Humanized Mouse Models for HIV Research: NIH/NIAID “Meet the Experts” 2015 Workshop Summary

Akkina, Ramesh; Allam, Atef; Balazs, Alejandro B.; Blankson, Joel N.; Burnett, J.; Casares, Sofía; García, J. Víctor; Hasenkrug, Kim J.; Kashanchi, Fatah; Kitchen, Scott G.; Klein, Florian; Kumar, Priti; Luster, Andrew D.; Poluektova, Larisa Y.; Rao, Mangala; Sanders-Beer, Brigitte E.; Shultz, Leonard D.; Zack, Jerome A.

doi:10.1089/aid.2015.0258

Cited by 58 publications

(57 citation statements)

References 76 publications

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“…Research in rodent models has been stimulated by improvements in the efficiency and stability of human haematopoietic stem cell grafts into immunodeficient mice 203,204 . NOD/Scid IL-2R-gamma null (NSG) mice that are engrafted with human CD34 + stem cells (NSG-hCD34 + ), which differentiate into mature human T lymphocytes, monocytes and macrophages, can be efficiently infected with HIV in a sustained manner 203–206 .…”

Section: Animal Models Of Neuro-hivmentioning

confidence: 99%

HIV-associated neurocognitive disorder — pathogenesis and prospects for treatment

et al. 2016

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In the past two decades, several advancements have improved the care of HIV-infected individuals. Most importantly, the development and deployment of combination antiretroviral therapy (CART) has resulted in a dramatic decline in the rate of deaths from AIDS, so that people living with HIV today have nearly normal life expectancies if treated with CART. The term HIV-associated neurocognitive disorder (HAND) has been used to describe the spectrum of neurocognitive dysfunction associated with HIV infection. HIV can enter the CNS during early stages of infection, and persistent CNS HIV infection and inflammation probably contribute to the development of HAND. The brain can subsequently serve as a sanctuary for ongoing HIV replication, even when systemic viral suppression has been achieved. HAND can remain in patients treated with CART, and its effects on survival, quality of life and everyday functioning make it an important unresolved issue. In this Review, we describe the epidemiology of HAND, the evolving concepts of its neuropathogenesis, novel insights from animal models, and new approaches to treatment. We also discuss how inflammation is sustained in chronic HIV infection. Moreover, we suggest that adjunctive therapies -treatments targeting CNS inflammation and other metabolic processes, including glutamate homeostasis, lipid and energy metabolism -are needed to reverse or improve HAND-related neurological dysfunction. Competing interests statementThe authors declare no competing interests. HHS Public AccessAuthor manuscript Nat Rev Neurol. Author manuscript; available in PMC 2016 July 08. Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript chronic infection that can be managed, is associated with a near-normal lifespan and in which opportunistic infections are rare 1 .The first major advancement was an understanding of the direct relationship between HIV replication and subsequent immunological and clinical progression. This finding emphasized the need to completely suppress HIV replication in order to control disease progression.The second major advancement was the development and deployment of combination antiretroviral therapy (CART), which can provide effective systemic suppression of HIV replication. The introduction of CART in the mid-1990s resulted in a 50% decline in the rate of death from AIDS, substantial decreases in rates of maternal-infant transmission, reduced incidence of opportunistic infections, and a 40-50% decrease in the incidence of HIVassociated dementia (HAD), which was previously common and is the most severe form of cognitive impairment associated with the infection 2 .The third major change in the care of HIV+ patients was the ability to monitor the efficacy of CART through the reliable and widespread measurement of CD4 + helper T cells, plasma HIV RNA levels and antiretroviral resistance profiles, all of which are now fully integrated into routine clinical care in the developed world and used to optimize treatment for individual patients. Plasma viral l...

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Section: Animal Models Of Neuro-hivmentioning

confidence: 99%

HIV-associated neurocognitive disorder — pathogenesis and prospects for treatment

et al. 2016

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“…Several modifications have also been made to the existing strains by knocking out mouse MHC class I and class II genes to reduce the development of GVHD when human PBMC are engrafted as their primary xenotarget is the mouse MHC. The overall result is an increasing array of improved humanized mice with higher human immune cell engraftment levels and enhanced functionality that are becoming available to the scientific community [reviewed in (3, 4, 7)].…”

Section: Remaining Limitations and Future Directionsmentioning

confidence: 99%

“…When engrafted with human cells, tissues and immune systems, the biological responses in humanized mice more faithfully recapitulate that seen in humans than in any previous models of humanized mice (3–6). A recent NIH workshop focusing on HIV research has highlighted many of the new emerging models of immunodeficient IL2rg null mice that are being created to address some of the remaining limitations that are present in the basic models (7). …”

Section: Introductionmentioning

confidence: 99%

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Humanized Mouse Models of Clinical Disease

Walsh

Kenney

Jangalwe

et al. 2017

Annu. Rev. Pathol. Mech. Dis.

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453

384

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Immunodeficient mice engrafted with functional human cells and tissues, i.e., “humanized mice”, have become increasingly important as small pre-clinical animal models for the study of human diseases. Since the description of immunodeficient mice bearing mutations in the IL2 receptor common gamma chain (IL2rgnull) in the early 2000’s, investigators have been able to engraft murine recipients with human hematopoietic stem cells that develop into functional human immune systems. These mice can also be engrafted with human tissues such as islets, liver, skin, and most solid and hematologic cancers. Humanized mice are permitting significant progress in studies of human infectious disease, cancer, regenerative medicine, graft versus host disease, allergies, and immunity. Ultimately, use of humanized mice may lead to the implementation of truly “personalized” medicine in the clinic. This review discusses recent progress in the development and use of humanized mice, and highlights their utility for the study of human diseases.

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“…Peripheral blood was collected from surviving mice at weeks 10,15,20,25,30,35, and 36, and engraftment of human lymphocytes was analyzed by flow cytometry. At signs of debilitating pathology or at the end point analyses (36 weeks after HSCT), mice were sacrificed for collection of tissues.…”

Section: Analysis Of Immune Reconstitution By Flow Cytometrymentioning

confidence: 99%

Human Effector Memory T Helper Cells Engage with Mouse Macrophages and Cause Graft-versus-Host–Like Pathology in Skin of Humanized Mice Used in a Nonclinical Immunization Study

Sundarasetty

Volk

Theobald

et al. 2017

The American Journal of Pathology

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Humanized mice engrafted with human hematopoietic stem cells and developing functional human T-cell adaptive responses are in critical demand to test human-specific therapeutics. We previously showed that humanized mice immunized with long-lived induced-dendritic cells loaded with the pp65 viral antigen (iDCpp65) exhibited a faster development and maturation of T cells. Herein, we evaluated these effects in a long-term (36 weeks) nonclinical model using two stem cell donors to assess efficacy and safety. Relative to baseline, iDCpp65 immunization boosted the output of effector memory CD4 T cells in peripheral blood and lymph nodes. No weight loss, human malignancies, or systemic graft-versus-host (GVH) disease were observed. However, for one reconstitution cohort, some mice immunized with iDCpp65 showed GVH-like signs on the skin. Histopathology analyses of the inflamed skin revealed intrafollicular and perifollicular human CD4 cells near F4/80 mouse macrophages around hair follicles. In spleen, CD4 cells formed large clusters surrounded by mouse macrophages. In plasma, high levels of human T helper 2-type inflammatory cytokines were detectable, which activated in vitro the STAT5 pathway of murine macrophages. Despite this inflammatory pattern, human CD8 T cells from mice with GVH reacted against the pp65 antigen in vitro. These results uncover a dynamic cross-species interaction between human memory T cells and mouse macrophages in the skin and lymphatic tissues of humanized mice.

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Improvements and Limitations of Humanized Mouse Models for HIV Research: NIH/NIAID “Meet the Experts” 2015 Workshop Summary

Cited by 58 publications

References 76 publications

HIV-associated neurocognitive disorder — pathogenesis and prospects for treatment

HIV-associated neurocognitive disorder — pathogenesis and prospects for treatment

Humanized Mouse Models of Clinical Disease

Human Effector Memory T Helper Cells Engage with Mouse Macrophages and Cause Graft-versus-Host–Like Pathology in Skin of Humanized Mice Used in a Nonclinical Immunization Study

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