Host Restricted Poxviruses Produce Distinct Host Responses in an In Vivo Mouse Model with Implications for Future Use as HIV-1 Vaccine Vectors

2014 ◽  
Vol 30 (S1) ◽  
pp. A248-A248
Author(s):  
Kristy Offerman ◽  
Olivia Carulei ◽  
Armin Deffur ◽  
Nicola Douglass ◽  
Anna-Lise Williamson
Keyword(s):  
Mouse Model ◽  
Host Responses ◽  
Vaccine Vectors ◽  
Hiv 1

scholarly journals Blocking HIV-1 Infection by Chromosomal Integrative Expression of Human CD4 on the Surface of Lactobacillus acidophilus ATCC 4356

2019 ◽  
Vol 93 (8) ◽  
Author(s):  
Wenzhong Wei ◽  
Joshua Wiggins ◽  
Duoyi Hu ◽  
Vladimir Vrbanac ◽  
Dane Bowder ◽  
...  
Keyword(s):  
Mouse Model ◽  
Lactobacillus Acidophilus ◽  
Sexual Transmission ◽  
Effective Vaccine ◽  
Humanized Mouse ◽  
Humanized Mouse Model ◽  
Antiviral Proteins ◽  
Hiv 1

ABSTRACT Lactobacillus bacteria are potential delivery vehicles for biopharmaceutical molecules because they are well-recognized as safe microorganisms that naturally inhabit the human body. The goal of this study was to employ these lactobacilli to combat human immunodeficiency virus type 1 (HIV-1) infection and transmission. By using a chromosomal integration method, we engineered Lactobacillus acidophilus ATCC 4356 to display human CD4, the HIV-1 receptor, on the cell surface. Since human CD4 can bind to any infectious HIV-1 particles, the engineered lactobacilli can potentially capture HIV-1 of different subtypes and prevent infection. Our data demonstrate that the CD4-carrying bacteria are able to adsorb HIV-1 particles and reduce infection significantly in vitro and also block intrarectal HIV-1 infection in a humanized mouse model in preliminary tests in vivo. Our results support the potential of this approach to decrease the efficiency of HIV-1 sexual transmission. IMPORTANCE In the absence of an effective vaccine, alternative approaches to block HIV-1 infection and transmission with commensal bacteria expressing antiviral proteins are being considered. This report provides a proof-of-concept by using Lactobacillus bacteria stably expressing the HIV-1 receptor CD4 to capture and neutralize HIV-1 in vitro and in a humanized mouse model. The stable expression of antiviral proteins, such as CD4, following genomic integration of the corresponding genes into this Lactobacillus strain may contribute to the prevention of HIV-1 sexual transmission.

scholarly journals Activity of a Novel Combined Antiretroviral Therapy of Gemcitabine and Decitabine in a Mouse Model for HIV-1

2012 ◽  
Vol 56 (4) ◽  
pp. 1942-1948 ◽  
Author(s):  
Christine L. Clouser ◽  
Colleen M. Holtz ◽  
Mary Mullett ◽  
Daune L. Crankshaw ◽  
Jacquie E. Briggs ◽  
...  
Keyword(s):  
Cell Culture ◽  
Mouse Model ◽  
Drug Combination ◽  
Leukemia Virus ◽  
Treatment Options ◽  
Murine Aids ◽  
Approved Drugs ◽  
Number Of Treatment ◽  
Hiv 1

ABSTRACTThe emergence of drug resistance threatens to limit the use of current anti-HIV-1 drugs and highlights the need to expand the number of treatment options available for HIV-1-infected individuals. Our previous studies demonstrated that two clinically approved drugs, decitabine and gemcitabine, potently inhibited HIV-1 replication in cell culture through a mechanism that is distinct from the mechanisms for the drugs currently used to treat HIV-1 infection. We further demonstrated that gemcitabine inhibited replication of a related retrovirus, murine leukemia virus (MuLV),in vivousing the MuLV-based LP-BM5/murine AIDS (MAIDS) mouse model at doses that were not toxic. Since decitabine and gemcitabine inhibited MuLV and HIV-1 replication with similar potency in cell culture, the current study examined the efficacy and toxicity of the drug combination using the MAIDS model. The data demonstrate that the drug combination inhibited disease progression, as detected by histopathology, viral loads, and spleen weights, at doses lower than those that would be required if the drugs were used individually. The combination of decitabine and gemcitabine exerted antiviral activity at doses that were not toxic. These findings indicate that the combination of decitabine and gemcitabine shows potent antiretroviral activity at nontoxic doses and should be further investigated for clinical relevance.

scholarly journals Mouse Model of Cervicovaginal Toxicity and Inflammation for Preclinical Evaluation of Topical Vaginal Microbicides

2004 ◽  
Vol 48 (5) ◽  
pp. 1837-1847 ◽  
Author(s):  
Bradley J. Catalone ◽  
Tina M. Kish-Catalone ◽  
Lynn R. Budgeon ◽  
Elizabeth B. Neely ◽  
Maelee Ferguson ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Mouse Model ◽  
In Vitro Cytotoxicity ◽  
Model Systems ◽  
Vaginal Mucosa ◽  
Minimal Damage ◽  
Hiv 1 ◽  
Topical Microbicide

ABSTRACT Clinical trials evaluating the efficacy of nonoxynol-9 (N-9) as a topical microbicide concluded that N-9 offers no in vivo protection against human immunodeficiency virus type 1 (HIV-1) infection, despite demonstrated in vitro inactivation of HIV-1 by N-9. These trials emphasize the need for better model systems to determine candidate microbicide effectiveness and safety in a preclinical setting. To that end, time-dependent in vitro cytotoxicity, as well as in vivo toxicity and inflammation, associated with N-9 exposure were characterized with the goal of validating a mouse model of microbicide toxicity. In vitro studies using submerged cell cultures indicated that human cervical epithelial cells were inherently more sensitive to N-9-mediated damage than human vaginal epithelial cells. These results correlated with in vivo findings obtained by using Swiss Webster mice in which intravaginal inoculation of 1% N-9 or Conceptrol gel (containing 4% N-9) resulted in selective and acute disruption of the cervical columnar epithelial cells 2 h postapplication accompanied by intense inflammatory infiltrates within the lamina propria. Although damage to the cervical epithelium was apparent out to 8 h postapplication, these tissues resembled control tissue by 24 h postapplication. In contrast, minimal damage and infiltration were associated with both short- and long-term exposure of the vaginal mucosa to either N-9 or Conceptrol. These analyses were extended to examine the relative toxicity of polyethylene hexamethylene biguanide (PEHMB), a polybiguanide compound under evaluation as a candidate topical microbicide. In similar studies, in vivo exposure to 1% PEHMB caused minimal damage and inflammation of the genital mucosa, a finding consistent with the demonstration that PEHMB was >350-fold less cytotoxic than N-9 in vitro. Collectively, these studies highlight the murine model of toxicity as a valuable tool for the preclinical assessment of toxicity and inflammation associated with exposure to candidate topical microbicides.

Evaluating the Safety and Efficacy of Anti-HIV Transgenic Cells in a Humanized Mouse Model (NOD/SCIDγc−/−) for HIV Stem Cell Gene Therapy.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2352-2352
Author(s):  
Joseph S. Anderson ◽  
Jon Walker ◽  
Louisa Wirthlin ◽  
John Javien ◽  
Jan A. Nolta ◽  
...  
Keyword(s):  
T Cells ◽  
Immune System ◽  
B Cells ◽  
Mouse Model ◽  
Lentiviral Vector ◽  
Human Cd34 ◽  
Cell Engraftment ◽  
Anti Hiv ◽  
Hiv 1

Abstract In vivo mouse models for safety and efficacy studies of anti-HIV gene therapeutics have been lacking in their ability to evaluate normal systemic hematopoiesis with the development of a functional immune system. These deficiencies in modeling these normal and essential physiologies can now be generated in the recently developed NOD/SCIDγc−/− mouse model. Human CD34+ progenitor cells after intrahepatic injection will undergo multi-organ engraftment generating a functional thymus along with the production of T cells, B cells, and macrophages. Upon injection with various strains of HIV-1, engrafted mice display a disseminated infection due to viral replication in human T cells and macrophages. Infected mice acquire characteristics of increased viremia over time with human CD4+ T cell depletion. Anti-HIV immune responses can also be generated in mice with high viremia. Here we demonstrate the successful engraftment of NOD/SCIDγc−/− mice after injection with human CD34+ progenitor cells isolated from umbilical cord blood. Human cell engraftment was observed in both primary and secondary lymphoid organs including the bone marrow (B cells and macrophages), thymus (T cells), spleen (T cells and B cells), lymph nodes (T cells and B cells), and peripheral blood (T cells and B cells). Human CD34+ cells were found in the liver concluding either organ retention from the initial injection or circulation in the peripheral blood. After displaying a high level of engraftment (>50%), we are now able to proceed with evaluating a number of anti- HIV gene therapeutic constructs for pre-clinical testing. These lentiviral vector constructs include a CCR5 shRNA which has been previously shown to knock down complete expression of CCR5, a human/rhesus macaque chimeric isoform of TRIM5α capable of potently inhibiting HIV-1 infection at the pre-integration step, and combination constructs containing multiple anti-HIV genes. The NOD/SCIDγc−/− mouse model will allow us to evaluate both the safety of these various anti-HIV lentiviral constructs in generating normal functioning transgenic immune system cells and also the efficacy of these anti- HIV genes in inhibiting HIV-1 infection in vivo. With the ability to facilitate multilineage human cell engraftment with the susceptibility for HIV infection, this in vivo model allows for the evaluation of anti-HIV gene therapeutic constructs in a stem cell-based setting. Lentiviral vector transgenic cells can now be tested for their capacity for normal immune system reconstitution.

scholarly journals 580. In Vivo Analyses of Aptamers and siRNA Therapeutics Against HIV-1 in Humanized Mouse Model

2015 ◽  
Vol 23 ◽  
pp. S231
Author(s):  
Sangeetha Satheesan ◽  
Haitang Li ◽  
Mayumi Takahashi ◽  
Jiehua Zhou ◽  
John Burnett ◽  
...  
Keyword(s):  
Mouse Model ◽  
Humanized Mouse ◽  
Humanized Mouse Model ◽  
Hiv 1

scholarly journals IlvY is an important regulator of Shigella infection in vitro and in vivo

2020 ◽  
Author(s):  
Mayumi K. Holly ◽  
Mark C. Anderson ◽  
Lesley M. Rabago ◽  
Azadeh Saffarian ◽  
Benoit S. Marteyn ◽  
...  
Keyword(s):  
Mouse Model ◽  
Wide Spectrum ◽  
Treatment Options ◽  
Host Responses ◽  
Secretion Systems ◽  
Severe Diarrhea ◽  
Adult Mice ◽  
Enteric Infections

AbstractShigellosis results from oral ingestion of the Gram-negative bacteria Shigella, and symptoms include severe diarrhea and dysentery. In the absence of vaccines, small molecule antibacterial drugs have provided treatment options for shigellosis. However, Shigella drug resistance is rapidly emerging, and Shigella strains with resistance to both third-generation cephalosporins and azithromycin have been identified in Asia. A re-conceptualization is needed regarding the development of therapeutics that target bacterial pathogens in order to reduce resistance development and alteration of gut microbiota, which is depleted upon treatment with wide spectrum antibiotics, thereby increasing susceptibility to subsequent enteric infections. A more organism-specific approach is to develop agents targeting virulence factors such as toxins, adhesins, invasins, quorum sensing, and protein secretion systems. For Shigella, there is interest in targeting transcription factors essential for Shigella infection in vivo rather than specific effectors. Here we describe the importance of the Shigella transcription factor IlvY in Shigella virulence in vitro and in vivo. This work included the development of a novel, oral mouse model of Shigella infection with wild-type adult mice. Unlike previous models, mice do not require antibiotic pretreatment or diet modifications. This mouse model was used to demonstrate the importance of IlvY for Shigella in vivo survival and that deletion of ilvY impacts host responses to infection. These results illustrate that IlvY is a potential therapeutic target for the treatment of shigellosis. In addition, the novel mouse model provides an exciting new opportunity to investigate therapeutic efficacy against Shigella infection and host responses to infection.

scholarly journals The effect of HIV-1 Vif polymorphisms on A3G anti-viral activity in an in vivo mouse model

Retrovirology ◽  
2016 ◽  
Vol 13 (1) ◽  
Author(s):  
Cristhian Cadena ◽  
Spyridon Stavrou ◽  
Tomaz Manzoni ◽  
Shilpa S. Iyer ◽  
Frederic Bibollet-Ruche ◽  
...  
Keyword(s):  
Mouse Model ◽  
Viral Activity ◽  
Hiv 1

scholarly journals In Vivo CD40-CD154 (CD40 Ligand) Interaction Induces Integrated HIV Expression by APC in an HIV-1-Transgenic Mouse Model

2001 ◽  
Vol 166 (5) ◽  
pp. 3210-3217 ◽  
Author(s):  
Claire Chougnet ◽  
Corona Freitag ◽  
Marco Schito ◽  
Elaine K. Thomas ◽  
Alan Sher ◽  
...  
Keyword(s):  
Mouse Model ◽  
Transgenic Mouse ◽  
Cd40 Ligand ◽  
Transgenic Mouse Model ◽  
Ligand Interaction ◽  
Hiv 1

scholarly journals Multispecific anti-HIV duoCAR-T cells display broad in vitro antiviral activity and potent in vivo elimination of HIV-infected cells in a humanized mouse model

2019 ◽  
Vol 11 (504) ◽  
pp. eaav5685 ◽  
Author(s):  
Kim Anthony-Gonda ◽  
Ariola Bardhi ◽  
Alex Ray ◽  
Nina Flerin ◽  
Mengyan Li ◽  
...  
Keyword(s):  
T Cells ◽  
Mouse Model ◽  
Hiv Infection ◽  
Lentiviral Vectors ◽  
Car T ◽  
Anti Hiv ◽  
Hiv 1

Adoptive immunotherapy using chimeric antigen receptor–modified T cells (CAR-T) has made substantial contributions to the treatment of certain B cell malignancies. Such treatment modalities could potentially obviate the need for long-term antiretroviral drug therapy in HIV/AIDS. Here, we report the development of HIV-1–based lentiviral vectors that encode CARs targeting multiple highly conserved sites on the HIV-1 envelope glycoprotein using a two-molecule CAR architecture, termed duoCAR. We show that transduction with lentiviral vectors encoding multispecific anti-HIV duoCARs confer primary T cells with the capacity to potently reduce cellular HIV infection by up to 99% in vitro and >97% in vivo. T cells are the targets of HIV infection, but the transduced T cells are protected from genetically diverse HIV-1 strains. The CAR-T cells also potently eliminated PBMCs infected with broadly neutralizing antibody-resistant HIV strains, including VRC01/3BNC117-resistant HIV-1. Furthermore, multispecific anti-HIV duoCAR-T cells demonstrated long-term control of HIV infection in vivo and prevented the loss of CD4+T cells during HIV infection using a humanized NSG mouse model of intrasplenic HIV infection. These data suggest that multispecific anti-HIV duoCAR-T cells could be an effective approach for the treatment of patients with HIV-1 infection.

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