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Reactivation of HIV-1 proviruses in immune-compromised mice engrafted with human VOA-negative CD4+ T cells.

ABSTRACT: BACKGROUND:HIV-1 infection remains incurable on antiretroviral therapy (ART) due to virus latency. To date, enhanced co-culture assays, including viral outgrowth assays (VOA), are commonly used to measure HIV-1 latent reservoirs and evaluate latency-reversing agents (LRAs). However, VOA can only reactivate a small fraction of intact proviruses. METHODS:To explore the utility of NOD scid gamma (NSG) mice as an in vivo model to reactivate HIV-1 proviruses from VOA-negative CD4+ T cells, resting CD4+ T cells from an HIV-1 latently infected individual were isolated and the human CD4+ T cells corresponding to VOA-positive and VOA-negative CD4+ T cells were engrafted into NSG mice. Plasma viral load (pVL) and human CD4+ T cells were quantified every other week using qRT-PCR and flow cytometry. RESULTS:We found that NSG mice reactivated latently infected HIV-1 from VOA-positive CD4+ T cells as well as VOA-negative CD4+ T cells. Engrafted CD4+ T cells proliferated considerably in vivo, peaked prior to provirus reactivation, and lasted for up to 14 weeks. Sequence analyses revealed that reactivated proviruses in VOA-positive and VOA-negative CD4+ T cells are different. CONCLUSION:Taken together, NSG mice can support long-term engraftment of human CD4+ T cells and reactivate VOA-positive and VOA-negative proviruses. Therefore, this in vivo model has the potential to be used to study the underlying mechanisms of HIV-1 latency and reactivation.

SUBMITTER: Yuan Z

PROVIDER: S-EPMC5337423 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Reactivation of HIV-1 proviruses in immune-compromised mice engrafted with human VOA-negative CD4+ T cells.

Yuan Zhe Z Kang Guobin G Lu Wuxun W Li Qingsheng Q

Journal of virus eradication 20170101 1

<h4>Background</h4>HIV-1 infection remains incurable on antiretroviral therapy (ART) due to virus latency. To date, enhanced co-culture assays, including viral outgrowth assays (VOA), are commonly used to measure HIV-1 latent reservoirs and evaluate latency-reversing agents (LRAs). However, VOA can only reactivate a small fraction of intact proviruses.<h4>Methods</h4>To explore the utility of NOD scid gamma (NSG) mice as an <i>in vivo</i> model to reactivate HIV-1 proviruses from VOA-negative CD ...[more]

PMID: 28275460

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Project description:Human liver chimeric mice are useful models of human hepatitis virus infection, including hepatitis B and C virus infections. Independently, immunodeficient mice reconstituted with CD34(+) hematopoietic stem cells (HSC) derived from fetal liver reliably develop human T and B lymphocytes. Combining these systems has long been hampered by inefficient liver reconstitution of human fetal hepatoblasts. Our study aimed to enhance hepatoblast engraftment in order to create a mouse model with syngeneic human liver and immune cells.The effects of human oncostatin-M administration on fetal hepatoblast engraftment into immunodeficient fah(-/-) mice was tested. Mice were then transplanted with syngeneic human hepatoblasts and HSC after which human leukocyte chimerism and functionality were analyzed by flow cytometry, and mice were challenged with HBV.Addition of human oncostatin-M enhanced human hepatoblast engraftment in immunodeficient fah(-/-) mice by 5-100 fold. In contrast to mice singly engrafted with HSC, which predominantly developed human T and B lymphocytes, mice co-transplanted with syngeneic hepatoblasts also contained physiological levels of human monocytes and natural killer cells. Upon infection with HBV, these mice displayed rapid and sustained viremia.Our study provides a new mouse model with improved human fetal hepatoblast engraftment and an expanded human immune cell repertoire. With further improvements, this model may become useful for studying human immunity against viral hepatitis.Important human pathogens such as hepatitis B virus, hepatitis C virus and human immunodeficiency virus only infect human cells which complicates the development of mouse models for the study of these pathogens. One way to make mice permissive for human pathogens is the transplantation of human cells into immune-compromised mice. For instance, the transplantation of human liver cells will allow the infection of these so-called "liver chimeric mice" with hepatitis B virus and hepatitis C virus. The co-transplantation of human immune cells into liver chimeric mice will further allow the study of human immune responses to hepatitis B virus or hepatitis C virus. However, for immunological studies it will be crucial that the transplanted human liver and immune cells are derived from the same human donor. In our study we describe the efficient engraftment of human fetal liver cells and immune cells derived from the same donor into mice. We show that liver co-engraftment resulted in an expanded human immune cell repertoire, including monocytes and natural killer cells in the liver. We further demonstrate that these mice could be infected with hepatitis B virus, which lead to an expansion of natural killer cells. In conclusion we have developed a new mouse model that could be useful to study human immune responses to human liver pathogens.

Dataset Information

Reactivation of HIV-1 proviruses in immune-compromised mice engrafted with human VOA-negative CD4+ T cells.

Publications

Reactivation of HIV-1 proviruses in immune-compromised mice engrafted with human VOA-negative CD4+ T cells.

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