scholarly journals Cellular HIV Reservoirs and Viral Rebound from the Lymphoid Compartments of 4′-Ethynyl-2-Fluoro-2′-Deoxyadenosine (EFdA)-Suppressed Humanized Mice

Viruses ◽  
2019 ◽  
Vol 11 (3) ◽  
pp. 256 ◽  
Author(s):  
Ekaterina Maidji ◽  
Mary Moreno ◽  
Jose Rivera ◽  
Pheroze Joshi ◽  
Sofiya Galkina ◽  
...  
Keyword(s):  
Transcriptase Inhibitor ◽  
Humanized Mice ◽  
In Vivo Model ◽  
Lymphoid Tissues ◽  
Viral Rebound ◽  
Hiv Reverse Transcriptase ◽  
Hiv Reservoirs ◽  
Hiv Reservoir ◽  
Drug Cessation

Although antiretroviral therapy (ART) greatly suppresses HIV replication, lymphoid tissues remain a sanctuary site where the virus may replicate. Tracking the earliest steps of HIV spread from these cellular reservoirs after drug cessation is pivotal for elucidating how infection can be prevented. In this study, we developed an in vivo model of HIV persistence in which viral replication in the lymphoid compartments of humanized mice was inhibited by the HIV reverse transcriptase inhibitor 4′-ethynyl-2-fluoro-2′-deoxyadenosine (EFdA) to very low levels, which recapitulated ART-suppression in HIV-infected individuals. Using a combination of RNAscope in situ hybridization (ISH) and immunohistochemistry (IHC), we quantitatively investigated the distribution of HIV in the lymphoid tissues of humanized mice during active infection, EFdA suppression, and after drug cessation. The lymphoid compartments of EFdA-suppressed humanized mice harbored very rare transcription/translation-competent HIV reservoirs that enable viral rebound. Our data provided the visualization and direct measurement of the early steps of HIV reservoir expansion within anatomically intact lymphoid tissues soon after EFdA cessation and suggest a strategy to enhance therapeutic approaches aimed at eliminating the HIV reservoir.

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

Viruses ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 776
Author(s):  
Kazutaka Terahara ◽  
Ryutaro Iwabuchi ◽  
Yasuko Tsunetsugu-Yokota
Keyword(s):  
Mouse Models ◽  
Humanized Mice ◽  
Lymphoid Tissues ◽  
Humanized Mouse ◽  
Hiv Pathogenesis ◽  
Hematopoietic Stem ◽  
Critical Issues ◽  
In Vivo Animal Models ◽  
Humanized Mouse Models

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.

scholarly journals Experimental transmission and pathogenesis of immunodeficiency syndrome in cats

Blood ◽  
1987 ◽  
Vol 70 (6) ◽  
pp. 1880-1892 ◽  
Author(s):  
EA Hoover ◽  
JI Mullins ◽  
SL Quackenbush ◽  
PW Gasper
Keyword(s):  
Viral Replication ◽  
Opportunistic Infections ◽  
Feline Leukemia Virus ◽  
In Vivo Model ◽  
Lymphoid Tissues ◽  
Experimental Transmission ◽  
Lymphoid Follicles ◽  
Immunodeficiency Disease ◽  
Immunodeficiency Syndrome

Abstract We describe the identification, experimental transmission, and pathogenesis of a naturally occurring powerfully immunosuppressive isolate of feline leukemia virus (designated here as FeLV-FAIDS) which induces fatal acquired immunodeficiency syndrome (AIDS) in 100% (25 of 25) of persistently viremic experimentally infected specific pathogen- free (SPF) cats after predictable survival periods ranging from less than 3 months (acute immunodeficiency syndrome) to greater than one year (chronic immunodeficiency syndrome), depending on the age of the cat at time of virus exposure. The pathogenesis of FeLV-FAIDS-induced feline immunodeficiency disease is characterized by: a prodromal period of largely asymptomatic viremia; progressive weight loss, lymphoid hyperplasia associated with viral replication in lymphoid follicles, lymphoid depletion associated with extinction of viral replication in lymphoid follicles, intractable diarrhea associated with necrosis of intestinal crypt epithelium, lymphopenia, suppressed lymphocyte blastogenesis, impaired cutaneous allograft rejection, hypogammaglobulinemia, and opportunistic infections such as bacterial respiratory disease and necrotizing stomatitis. The clinical onset of immunodeficiency syndrome correlates with the replication of a specific FeLV-FAIDS viral variant, detected principally as unintegrated viral DNA, in bone marrow, lymphoid tissues, and intestine. Two of seven cats with chronic immunodeficiency disease that survived greater than 1 year after inoculation developed lymphoma affecting the marrow, intestine, spleen, and mesenteric nodes. Experimentally induced feline immunodeficiency syndrome, therefore, is a rapid and consistent in vivo model for prospective studies of the viral genetic determinants, pathogenesis, prevention, and therapy of retrovirus-induced immunodeficiency disease.

Macrophages Prevent Human Red Blood Cell Reconstitution In NOD/SCID and NOD/SCID/γc−/− Mice.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3723-3723
Author(s):  
Zheng Hu ◽  
Yong-Guang Yang
Keyword(s):  
Mononuclear Cells ◽  
Conflicts Of Interest ◽  
Embryonic Stem ◽  
Humanized Mice ◽  
In Vivo Model ◽  
Recipient Mouse ◽  
Hematopoietic Stem ◽  
Immunodeficient Mice ◽  
Human Rbcs

Abstract Abstract 3723 An animal model supporting human erythropoiesis will be highly valuable for assessing the biological function of human RBCs under physiological and disease settings, and for evaluating protocols of in vitro RBC differentiation from human embryonic stem cells. Although immunodeficient mice on the NOD background have been widely used to study human hematopoietic stem cell function in vivo, the successful use of these mice in the study of human erythropoiesis and RBC function has not been reported. We have previously shown that co-transplantation of human fetal thymic tissue (under renal capsule) and CD34+ fetal liver cells (FLCs; i.v.) in NOD/SCID or NOD/SCID/γc−/− mice results in the development of multilineage human hematopoietic cells. Here, we analyzed human RBC reconstitution in these humanized mice. Although a large number of human erythrocytes, which consisted predominantly of immature nucleated erythrocytes, were detected in the bone marrow of human fetal thymus/CD34+ FLC-grafted mice, human RBCs were undetectable in blood of these mice, even in those with nearly full human chimerism in peripheral blood mononuclear cells (PBMCs). Recipient mouse macrophage-mediated rejection is, at least, one of the major mechanisms responsible for the lack of human RBCs in these mice, as human RBCs became detectable in blood following macrophage depletion and disappeared again after withdrawal of treatment. Furthermore, treatment with human erythropoietin (EPO) and human IL-3 significantly increased human RBC reconstitution in mice that were depleted of macrophages. Like the human RBCs developed in the humanized mice, exogenously injected normal human RBCs were also rapidly rejected by macrophages in NOD/SCID mice. Taken together, our data demonstrate that human RBCs are highly susceptible to rejection by macrophages in immunodeficient mice. Thus, strategies for preventing human RBC rejection by macrophages are required for using immunodeficient mice as an in vivo model to study human erythropoiesis and RBC function. Disclosures: No relevant conflicts of interest to declare.

A novel in vivo model for predicting myelotoxicity of chemotherapeutic agents using IL-3/GM-CSF transgenic humanized mice

2017 ◽  
Vol 281 ◽  
pp. 152-157 ◽  
Author(s):  
R. Ito ◽  
D. Nagai ◽  
N. Igo ◽  
Y. Okuda ◽  
K. Sekine ◽  
...  
Keyword(s):  
Chemotherapeutic Agents ◽  
Humanized Mice ◽  
In Vivo Model ◽  
Gm Csf

scholarly journals An In Vivo Model of Wound Healing in Genetically Modified Skin-Humanized Mice

2004 ◽  
Vol 123 (6) ◽  
pp. 1182-1191 ◽  
Author(s):  
María José Escámez ◽  
Marta García ◽  
Fernando Larcher ◽  
Alvaro Meana ◽  
Evangelina Muñoz ◽  
...  
Keyword(s):  
Wound Healing ◽  
Genetically Modified ◽  
Humanized Mice ◽  
In Vivo Model

scholarly journals The combination of the NS5A and cyclophilin inhibitors results in an additive anti-HCV inhibition in humanized mice without development of resistance

PLoS ONE ◽  
2021 ◽  
Vol 16 (5) ◽  
pp. e0251934
Author(s):  
Michael Bobardt ◽  
Christina M. Ramirez ◽  
Marc M. Baum ◽  
Daren Ure ◽  
Robert Foster ◽  
...  
Keyword(s):  
Humanized Mice ◽  
Viral Rebound ◽  
Viral Response ◽  
Development Of Resistance ◽  
Sustain Viral Response ◽  
Direct Acting ◽  
Selection Of ◽  
Selection Of Resistance

We and others previously reported that the direct-acting agents (DAA) NS5A inhibitors (NS5Ai) and the host-targeting agents cyclophilin inhibitors (CypIs) inhibit HCV replication in vitro. In this study, we investigated whether the combination of NS5Ai and CypI offers a potent anti-HCV effect in vivo. A single administration of NS5Ai or CypI alone to HCV-infected humanized-mice inhibits HCV replication. The combination of NS5Ai with CypI suppresses HCV (GT1a, GT2a, GT3a and GT4a) replication in an additive manner. NS5Ai/CypI combinations provide a statistically more profound anti-HCV inhibition for GT2a and GT3a than GT1a and GT4a, leading to a fastest and deepest inhibition of GT2a and GT3a replications. Combining CypI with NS5Ai prevents the viral rebound normally observed in mice treated with NS5Ai alone. Results were confirmed in mice implanted with human hepatocytes from different donors. Therefore, the combination of NS5Ai with CypI may serve as a regimen for the treatment of HCV patients with specific genotypes and disorder conditions, which diminish sustain viral response levels to DAA, such as GT3a infection, cirrhosis, and DAA resistance associated with the selection of resistance-associated substitutions present at baseline or are acquired during treatment.

scholarly journals Saquinavir-mediated inhibition of human immunodeficiency virus (HIV) infection in SCID mice implanted with human fetal thymus and liver tissue: an in vivo model for evaluating the effect of drug therapy on HIV infection in lymphoid tissues.

1997 ◽  
Vol 41 (9) ◽  
pp. 1880-1887 ◽  
Author(s):  
M Pettoello-Mantovani ◽  
T R Kollmann ◽  
C Raker ◽  
A Kim ◽  
S Yurasov ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Hiv Infection ◽  
Scid Mice ◽  
Therapeutic Interventions ◽  
In Vivo Model ◽  
Lymphoid Tissues ◽  
Hiv Replication ◽  
Viral Loads ◽  
Immunodeficiency Virus

Treatment with protease inhibitors alone or in combination with inhibitors of reverse transcriptase potently suppresses levels of human immunodeficiency virus (HIV) RNA in plasma and thereby may significantly delay the progression of HIV-mediated disease. To investigate the effect of treatment with the protease inhibitor saquinavir on HIV replication in the lymphoid tissues, we used a SCID-hu mouse model that we developed, in which human thymic and liver tissues (hu-thy/liv) were implanted under both kidney capsules in SCID mice (thy/liv-SCID-hu mice). These mice are populated in the periphery with large numbers of human T cells and develop disseminated HIV infection after intraimplant injection. thy/liv-SCID-hu mice with established HIV infection that were treated for 1 month with saquinavir had a significantly lower viral load present in the implanted hu-thy/liv and mouse spleen than did the untreated HIV-infected thy/liv-SCID-hu mice. To examine the capacity of acute treatment with saquinavir to prevent HIV infection, some thy/liv-SCID-hu mice were inoculated with HIV and then immediately started on saquinavir. Although treated mice had markedly lower viral loads in the thy/liv implants and spleens, HIV infection was not completely prevented. Thus, the effect of antiviral therapy on HIV infection in the major site of HIV replication, the lymphoid tissues, can be readily evaluated in our thy/liv-SCID-hu mice. These mice should prove to be a useful model for determining the in vivo effectiveness of different therapeutic interventions on acute and chronic HIV infection.

scholarly journals Experimental transmission and pathogenesis of immunodeficiency syndrome in cats

Blood ◽  
1987 ◽  
Vol 70 (6) ◽  
pp. 1880-1892
Author(s):  
EA Hoover ◽  
JI Mullins ◽  
SL Quackenbush ◽  
PW Gasper
Keyword(s):  
Viral Replication ◽  
Opportunistic Infections ◽  
Feline Leukemia Virus ◽  
In Vivo Model ◽  
Lymphoid Tissues ◽  
Experimental Transmission ◽  
Lymphoid Follicles ◽  
Immunodeficiency Disease ◽  
Immunodeficiency Syndrome

We describe the identification, experimental transmission, and pathogenesis of a naturally occurring powerfully immunosuppressive isolate of feline leukemia virus (designated here as FeLV-FAIDS) which induces fatal acquired immunodeficiency syndrome (AIDS) in 100% (25 of 25) of persistently viremic experimentally infected specific pathogen- free (SPF) cats after predictable survival periods ranging from less than 3 months (acute immunodeficiency syndrome) to greater than one year (chronic immunodeficiency syndrome), depending on the age of the cat at time of virus exposure. The pathogenesis of FeLV-FAIDS-induced feline immunodeficiency disease is characterized by: a prodromal period of largely asymptomatic viremia; progressive weight loss, lymphoid hyperplasia associated with viral replication in lymphoid follicles, lymphoid depletion associated with extinction of viral replication in lymphoid follicles, intractable diarrhea associated with necrosis of intestinal crypt epithelium, lymphopenia, suppressed lymphocyte blastogenesis, impaired cutaneous allograft rejection, hypogammaglobulinemia, and opportunistic infections such as bacterial respiratory disease and necrotizing stomatitis. The clinical onset of immunodeficiency syndrome correlates with the replication of a specific FeLV-FAIDS viral variant, detected principally as unintegrated viral DNA, in bone marrow, lymphoid tissues, and intestine. Two of seven cats with chronic immunodeficiency disease that survived greater than 1 year after inoculation developed lymphoma affecting the marrow, intestine, spleen, and mesenteric nodes. Experimentally induced feline immunodeficiency syndrome, therefore, is a rapid and consistent in vivo model for prospective studies of the viral genetic determinants, pathogenesis, prevention, and therapy of retrovirus-induced immunodeficiency disease.

scholarly journals Human NK cell development in hIL-7 and hIL-15 knockin NOD/SCID/IL2rgKO mice

2019 ◽  
Vol 2 (2) ◽  
pp. e201800195 ◽  
Author(s):  
Masashi Matsuda ◽  
Rintaro Ono ◽  
Tomonori Iyoda ◽  
Takaho Endo ◽  
Makoto Iwasaki ◽  
...  
Keyword(s):  
Nk Cells ◽  
Immune Cells ◽  
Nk Cell ◽  
Cell Development ◽  
Innate Immune ◽  
Humanized Mice ◽  
In Vivo Model ◽  
Hematopoietic Stem ◽  
Nsg Mice

The immune system encompasses acquired and innate immunity that matures through interaction with microenvironmental components. Cytokines serve as environmental factors that foster functional maturation of immune cells. Although NOD/SCID/IL2rgKO (NSG) humanized mice support investigation of human immunity in vivo, a species barrier between human immune cells and the mouse microenvironment limits human acquired as well as innate immune function. To study the roles of human cytokines in human acquired and innate immune cell development, we created NSG mice expressing hIL-7 and hIL-15. Although hIL-7 alone was not sufficient for supporting human NK cell development in vivo, increased frequencies of human NK cells were confirmed in multiple organs of hIL-7 and hIL-15 double knockin (hIL-7xhIL-15 KI) NSG mice engrafted with human hematopoietic stem cells. hIL-7xhIL-15 KI NSG humanized mice provide a valuable in vivo model to investigate development and function of human NK cells.

scholarly journals Longitudinal bioluminescent imaging of HIV-1 infection during antiretroviral therapy and treatment interruption in humanized mice

2019 ◽  
Author(s):  
John D. Ventura ◽  
Jagadish Beloor ◽  
Edward Allen ◽  
Tongyu Zhang ◽  
Kelsey A. Haugh ◽  
...  
Keyword(s):  
Antiretroviral Therapy ◽  
Humanized Mice ◽  
Lymphoid Tissues ◽  
Bioluminescent Imaging ◽  
Viral Spread ◽  
Non Invasive ◽  
Infection Dynamics ◽  
Infected Cells ◽  
Hiv 1

AbstractNon-invasive bioluminescent imaging (NIBLI) of HIV-1 infection dynamics allows for real-time monitoring of viral spread and the localization of infected cell populations in living animals. In this report, we describe full-length replication-competent GFP and Nanoluciferase (Nluc) expressing HIV-1 reporter viruses from two clinical transmitted / founder (T/F) stains: TRJO.c and Q23.BG505. By infecting humanized mice with these HIV-1 T/F reporter viruses, we were able to directly monitor longitudinal viral spread at whole-animal resolution via NIBLI at a sensitivity of as few as 30-50 infected cells. Bioluminescent signal strongly correlated with HIV-1 infection and responded proportionally to virus suppression in vivo in animals treated daily with a combination antiretroviral therapy (cART) regimen. Longitudinal NIBLI following cART withdrawal visualized tissue-sites that harbored virus during infection recrudescence. Notably, we observed rebounding infection in the same lymphoid tissues where infection was first observed prior to ART treatment. Our work demonstrates the utility of our system for studying in vivo viral infection dynamics and identifying infected tissue regions for subsequent analyses.Author SummaryNon-invasive bioluminescent imaging (NIBLI) in small animals allows for in vivo longitudinal imaging of infection spread and pathogenesis. We have taken advantage of the small luciferase reporter protein, Nanoluciferase (Nluc), to generate a replication-competent HIV-1 reporter virus to allow for NIBLI of viral infection in humanize mice. NIBLI via Nluc enabled us to directly visualize longitudinal spreading patterns before, during, and after interruption of daily doses of combined antiretroviral therapy (cART). We observed that rebounding infection often emerged in tissue regions originally associated with infected cells prior to cART treatment. Thus, Nluc-based NIBLI of HIV-1 infection can be used as an experimental tool to study early events involved in viral dissemination and spread from initial sites of infection to draining lymphoid tissues as well as locate infected tissues for subsequent cellular characterization of HIV-1 infected cells.

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