Studies of retroviral infection in humanized mice

Marsden, Matthew D.; Zack, Jerome A.

doi:10.1016/j.virol.2015.01.017

Cited by 38 publications

(45 citation statements)

References 168 publications

(180 reference statements)

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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%

“…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 . Chronic HIV infection in this model is characterized by high HIV plasma burdens, CD4 + T cell depletion, and low-level HIV neuroinvasion 205,206 .…”

Section: Animal Models Of Neuro-hivmentioning

confidence: 99%

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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%

Section: Animal Models Of Neuro-hivmentioning

confidence: 99%

HIV-associated neurocognitive disorder — pathogenesis and prospects for treatment

et al. 2016

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“…The results of this study indicate that no current in vitro latency model faithfully recapitulates the nature of the HIV-1 latent reservoir. Pre-clinical research on LRA efficacy and toxicity gathered from non-human primate SIV models[91, 92], humanized mouse models[93–96] and purified resting CD4 + T cells obtained from HIV-1 infected, aviremic patients[97, 98] are current strategies addressing this significant knowledge gap (see Boxes 1, 2). …”

Section: First Do No Harm: Clinical Trial Outcomesmentioning

confidence: 99%

HIV-1 Eradication: Early Trials (and Tribulations)

Spivak

Planelles

2016

Trends in Molecular Medicine

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Antiretroviral therapy (ART) has rendered HIV-1 infection a manageable illness for those with access to treatment. However, ART does not lead to viral eradication due to the persistence of replication-competent, unexpressed proviruses in long-lived cellular reservoirs. The potential for long-term drug toxicities and the lack of access to ART for most people living with HIV-1 infection have fueled scientific interest in understanding the nature of this latent reservoir. Exploration of HIV-1 persistence at the cellular and molecular level in resting memory CD4+ T cells, the predominant viral reservoir in patients on ART, has uncovered potential strategies to reverse latency. Here, we review recent advances in pharmacologically-based ‘shock and kill’ HIV-1 eradication strategies, including comparative analysis of early clinical trials.

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“…It is particularly useful for studies of human immunodeficiency virus (HIV) infection because of the high frequencies of human T cells in the lymphoid and mucosal tissues of BLT mice, as well as because of the proper maturation status and lineage differentiation of these human T cells [14][15][16]. To date, studies using BLT mice have generated valuable knowledge in many aspects of HIV infection, including prevention, mucosal transmission, HIV-specific innate and adaptive immunity, viral latency, and novel anti-retroviral and immune-based therapies for suppression and reservoir eradication [14][15][16][17]. The humanized BLT mouse model is also ideal for the study of hematopoietic stem cell (HSC)-and T cell-based immunotherapies, because of the long-term engraftment of human HSCs and T cells in BLT mice [10,11].…”

Section: /Il-2rgmentioning

confidence: 99%

Propagating Humanized BLT Mice for the Study of Human Immunology and Immunotherapy

SmithDrake

LinLevina

MoonHeesung

et al. 2016

Stem Cells and Development

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The humanized bone marrow-liver-thymus (BLT) mouse model harbors a nearly complete human immune system, therefore providing a powerful tool to study human immunology and immunotherapy. However, its application is greatly limited by the restricted supply of human CD34+ hematopoietic stem cells and fetal thymus tissues that are needed to generate these mice. The restriction is especially significant for the study of human immune systems with special genetic traits, such as certain human leukocyte antigen (HLA) haplotypes or monogene deficiencies. To circumvent this critical limitation, we have developed a method to quickly propagate established BLT mice. Through secondary transfer of bone marrow cells and human thymus implants from BLT mice into NSG (NOD/SCID/IL-2Rg -/-) recipient mice, we were able to expand one primary BLT mouse into a colony of 4-5 proBLT (propagated BLT) mice in 6-8 weeks. These proBLT mice reconstituted human immune cells, including T cells, at levels comparable to those of their primary BLT donor mouse. They also faithfully inherited the human immune cell genetic traits from their donor BLT mouse, such as the HLA-A2 haplotype that is of special interest for studying HLA-A2-restricted human T cell immunotherapies. Moreover, an EGFP reporter gene engineered into the human immune system was stably passed from BLT to proBLT mice, making proBLT mice suitable for studying human immune cell gene therapy. This method provides an opportunity to overcome a critical hurdle to utilizing the BLT humanized mouse model and enables its more widespread use as a valuable preclinical research tool.

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Studies of retroviral infection in humanized mice

Cited by 38 publications

References 168 publications

HIV-associated neurocognitive disorder — pathogenesis and prospects for treatment

HIV-associated neurocognitive disorder — pathogenesis and prospects for treatment

HIV-1 Eradication: Early Trials (and Tribulations)

Propagating Humanized BLT Mice for the Study of Human Immunology and Immunotherapy

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