Humanized mice dually challenged with R5 and X4 HIV-1 show preferential R5 viremia and restricted X4 infection of CCR5+CD4+ T cells

Terahara, Kazutaka; Ishige, Masayuki; Ikeno, Shota; Okada, Seiji; Kobayashi-Ishihara, Mie; Ato, Manabu; Tsunetsugu-Yokota, Yasuko

doi:10.1016/j.micinf.2015.02.002

Cited by 8 publications

(9 citation statements)

References 45 publications

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“…However, in contrast to that in humans, the viral setpoint is not obvious and the higher level of viremia continues as long as CD4 + T-cell hematopoiesis is maintained [ 70 , 75 , 87 ]. Whereas our group and Akkina’s group reported that R5 HIV-1 replicates more than X4 HIV-1 in humanized mice [ 68 , 72 , 73 , 77 ], some research groups have shown similar replication levels for R5 and X4 viruses [ 42 , 70 , 87 ]. This discrepancy might be due to the different experimental conditions used, including the type of HIV-1 strain and the status of the humanized mice.…”

Section: Dynamics Of Plasma Viral Load In Hiv-challenged Humanized Micementioning

confidence: 82%

“…At the end of this phase, plasma HIV-1 can be detected and increases exponentially, peaking at 21–28 days post-infection [ 65 , 66 , 67 ]. In humanized mice, viremia is usually observed as early as 1 week after inoculation, regardless of the route of inoculation (intravenously, intraperitoneally, intrarectally, or intravaginally) and viral tropism (CCR5-tropic: R5; CXCR4-tropic: X4; or dual-tropic) [ 5 , 38 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 ]. It should be noted that plasma HIV-1 detected before 1 week may represent the inoculated viruses, because we observed that, when non-humanized NOJ mice were challenged with 2 to 50 ng of p24-measured amounts of HIV-1 intravenously or intraperitoneally, plasma HIV-1 was detected up to 5 days post-challenge for any HIV-1 dose inoculation (data not shown).…”

Section: Dynamics Of Plasma Viral Load In Hiv-challenged Humanized Micementioning

confidence: 99%

“…It is known that activated memory CD4 + T cells express more CCR5 but less CXCR4, resulting in them being more permissive to R5 HIV-1 but more restrictive for X4 HIV-1 [ 88 , 89 ]. Furthermore, when we investigated CB-HSC-NOJ mice that were singly or simultaneously infected with R5 HIV-1 and X4 HIV-1 using isogenic virus strains harboring DsRed or EGFP (R5: NL-AD8-D or X4: NL-E, respectively), we found that the X4 HIV-1 infection of CCR5 + CD4 + T cells was suppressed in the presence of R5 HIV-1 [ 77 ]. As CCR5 + CD4 + T cells would be a major producer of HIV-1 on the basis of their higher activation level, our previous finding would provide an insight into a mechanism by which R5 HIV-1 is dominantly isolated during the early stage of infection in patients [ 90 , 91 , 92 ], despite the fact that newly infected individuals have usually been exposed to a mixture of R5 and X4 viruses [ 93 , 94 , 95 , 96 ].…”

Section: Dynamics Of Plasma Viral Load In Hiv-challenged Humanized Micementioning

confidence: 99%

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Perspectives on Non-BLT Humanized Mouse Models for Studying HIV Pathogenesis and Therapy

Terahara

Iwabuchi

Tsunetsugu-Yokota

2021

Viruses

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A variety of humanized mice, which are reconstituted only with human hematopoietic stem cells (HSC) or with fetal thymus and HSCs, have been developed and widely utilized as in vivo animal models of HIV-1 infection. The models represent some aspects of HIV-mediated pathogenesis in humans and are useful for the evaluation of therapeutic regimens. However, there are several limitations in these models, including their incomplete immune responses and poor distribution of human cells to the secondary lymphoid tissues. These limitations are common in many humanized mouse models and are critical issues that need to be addressed. As distinct defects exist in each model, we need to be cautious about the experimental design and interpretation of the outcomes obtained using humanized mice. Considering this point, we mainly characterize the current conventional humanized mouse reconstituted only with HSCs and describe past achievements in this area, as well as the potential contributions of the humanized mouse models for the study of HIV pathogenesis and therapy. We also discuss the use of various technologies to solve the current problems. Humanized mice will contribute not only to the pre-clinical evaluation of anti-HIV regimens, but also to a deeper understanding of basic aspects of HIV biology.

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Section: Dynamics Of Plasma Viral Load In Hiv-challenged Humanized Micementioning

confidence: 82%

Section: Dynamics Of Plasma Viral Load In Hiv-challenged Humanized Micementioning

confidence: 99%

Section: Dynamics Of Plasma Viral Load In Hiv-challenged Humanized Micementioning

confidence: 99%

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Perspectives on Non-BLT Humanized Mouse Models for Studying HIV Pathogenesis and Therapy

Terahara

Iwabuchi

Tsunetsugu-Yokota

2021

Viruses

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“…Modeling HIV infection is one of the success stories for humanized mice, which has provided a sustainable model to study infection and a platform for testing several HIV/AIDS-related phenomenon [65][66][67][68][69]. Zika infection and related viremia have also been well studied in humanized models [70].…”

Section: Viral Sepsismentioning

confidence: 99%

Humanized Mice as a Tool to Study Sepsis—More Than Meets the Eye

Laudański

2021

IJMS

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(1) Background. Repetitive animal studies that have disappointed upon translation into clinical therapies have led to an increased appreciation of humanized mice as a remedy to the shortcomings of rodent-based models. However, their limitations have to be understood in depth. (2) Methods. This is a narrative, comprehensive review of humanized mice and sepsis literature to understand the model’s benefits and shortcomings. (3) Results: Studies involving humanized models of sepsis include bacterial, viral, and protozoan etiology. Humanized mice provided several unique insights into the etiology and natural history of sepsis and are particularly useful in studying Ebola, and certain viral and protozoan infections. However, studies are relatively sparse and based on several different models of sepsis and humanized animals. (4) Conclusions. The utilization of humanized mice as a model for sepsis presents complex limitations that, once surpassed, hold some potential for the advancement of sepsis etiology and treatment.

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“…In addition, xenotransplantation of human hematopoietic stem cells (HSCs) instead of human peripheral blood mononuclear cells into immunodeficient mice enables long-term and multi-lineage human hematopoiesis ( 17 – 21 ). Our research group has also developed a humanized mouse model using human HSC-transplanted NOD/SCID/Jak3 null (NOJ) mice ( 22 – 24 ). NOJ mice, which have an identical phenotype as NSG and NOG mice due to the deficiency of IL-2 downstream molecule Jak3, were developed as an alternative recipient mouse strain for humanization ( 25 ).…”

Section: Introductionmentioning

confidence: 99%

Introduction of Human Flt3-L and GM-CSF into Humanized Mice Enhances the Reconstitution and Maturation of Myeloid Dendritic Cells and the Development of Foxp3+CD4+ T Cells

et al. 2018

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Two cytokines, fms-related tyrosine kinase 3 ligand (Flt3-L) and granulocyte-macrophage colony-stimulating factor (GM-CSF) are considered to be the essential regulators of dendritic cell (DC) development in vivo. However, the combined effect of Flt3-L and GM-CSF on human DCs has not been evaluated in vivo. In this study, we, therefore, aimed at evaluating this using a humanized mouse model. Humanized non-obese diabetic/SCID/Jak3null (hNOJ) mice were constructed by transplanting hematopoietic stem cells from human umbilical cord blood into newborn NOJ mice, and in vivo transfection (IVT) was performed by hydrodynamic injection-mediated gene delivery using plasmids encoding human Flt3-L and GM-CSF. Following IVT, Flt3-L and GM-CSF were successfully induced in hNOJ mice. At 10 days post-IVT, we found, in the spleen, that treatment with both Flt3-L and GM-CSF enhanced the reconstitution of two myeloid DC subsets, CD14−CD1c+ conventional DCs (cDCs) and CD14−CD141+ cDCs, in addition to CD14+ monocyte-like cells expressing CD1c and/or CD141. GM-CSF alone had less effect on the reconstitution of these myeloid cell populations. By contrast, none of the cytokine treatments enhanced CD123+ plasmacytoid DC (pDC) reconstitution. Regardless of the reconstitution levels, three cell populations (CD1c+ myeloid cells, CD141+ myeloid cells, and pDCs) could be matured by treatment with cytokines, in terms of upregulation of CD40, CD80, CD86, and CD184/CXCR4 and downregulation of CD195/CCR5. In particular, GM-CSF contributed to upregulation of CD80 in all these cell populations. Interestingly, we further observed that Foxp3+ cells within splenic CD4+ T cells were significantly increased in the presence of GM-CSF. Foxp3+ T cells could be subdivided into two subpopulations, CD45RA−Foxp3hi and CD45RA−Foxp3lo T cells. Whereas CD45RA−Foxp3hi T cells were increased only after treatment with GM-CSF alone, CD45RA−Foxp3lo T cells were increased only after treatment with both Flt3-L and GM-CSF. Treatment with Flt3-L alone had no effect on the number of Foxp3+ T cells. The correlation analysis demonstrated that the development of these Foxp3+ subpopulations was associated with the maturation status of DC(-like) cells. Taken together, this study provides a platform for studying the in vivo effect of Flt3-L and GM-CSF on human DCs and regulatory T cells.

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Humanized mice dually challenged with R5 and X4 HIV-1 show preferential R5 viremia and restricted X4 infection of CCR5+CD4+ T cells

Cited by 8 publications

References 45 publications

Perspectives on Non-BLT Humanized Mouse Models for Studying HIV Pathogenesis and Therapy

Perspectives on Non-BLT Humanized Mouse Models for Studying HIV Pathogenesis and Therapy

Humanized Mice as a Tool to Study Sepsis—More Than Meets the Eye

Introduction of Human Flt3-L and GM-CSF into Humanized Mice Enhances the Reconstitution and Maturation of Myeloid Dendritic Cells and the Development of Foxp3+CD4+ T Cells

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