A model of human cytomegalovirus infection in severe combined immunodeficient mice

Bravo, Fernando; Cardin, Rhonda D.; Bernstein, David I.

doi:10.1016/j.antiviral.2007.06.008

Cited by 18 publications

(13 citation statements)

References 25 publications

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“…Consequently, we assessed the antiviral efficacy of AIC246 in an engineered mouse xenograft model (14). The Gelfoam xenograft model employed has two major advantages over other animal models: first, the appropriate human virus can be used for in vivo evaluation; second, antiviral compounds that show activity only against human cytomegalovirus can be tested (11). Using this animal model, AIC246 shows excellent antiviral efficacy.…”

Section: Discussionmentioning

confidence: 99%

In Vitro and In Vivo Activities of the Novel Anticytomegalovirus Compound AIC246

Lischka

Hewlett

Wunberg

et al. 2010

Antimicrob Agents Chemother

222

179

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Human cytomegalovirus (HCMV) remains a serious threat for immunocompromised individuals, including transplant recipients and newborns. To date, all drugs licensed for the treatment of HCMV infection and disease target the viral DNA polymerase. Although these drugs are effective, several drawbacks are associated with their use, including toxicity and emergence of drug resistance. Hence, new and improved antivirals with novel molecular targets are urgently needed. Here we report on the antiviral properties of AIC246, a representative of a novel class of low-molecular-weight compounds that is currently undergoing clinical phase II studies. The anti-HCMV activity of AIC246 was evaluated in vitro and in vivo using various cell culture assays and an engineered mouse xenograft model. In addition, antiviral properties of the drug were characterized in comparison to the current gold standard ganciclovir. We demonstrate that AIC246 exhibits excellent in vitro inhibitory activity against HCMV laboratory strains and clinical isolates, retains activity against ganciclovirresistant viruses, is well tolerated in different cell types (median selectivity index, 18,000), and exerts a potent in vivo efficacy in a mouse xenograft model. Moreover, we show that the antiviral block induced by AIC246 is reversible and the efficacy of the drug is not significantly affected by cell culture variations such as cell type or multiplicity of infection. Finally, initial mode-of-action analyses reveal that AIC246 targets a process in the viral replication cycle that occurs later than DNA synthesis. Thus, AIC246 acts via a mode of action that differs from that of polymerase inhibitors like ganciclovir.Human cytomegalovirus (HCMV) is a widespread opportunistic pathogen in immunocompromised individuals, including transplant recipients and tumor or AIDS patients, and remains the leading viral cause of birth defects (1,9,12,17,29). To date, a limited number of drugs are licensed for the systemic treatment of HCMV infection and disease: ganciclovir (GCV) (Cymevene; Roche), its oral prodrug valganciclovir (VGCV) (Valcyte; Roche), cidofovir (CDF) (Vistide; Gilead), and foscarnet (FOS) (Foscavir; Astra-Zeneca). In addition, valaciclovir (VACV) (Valtrex; GlaxoSmithKline), a drug that has been primarily developed for the treatment of herpes simplex virus (HSV) and varicella-zoster virus (VZV) infection, has gained marketing approval in certain countries for prophylaxis of HCMV infections in transplant patients. Although GCV, VGCV, CDF, and FOS are effective, several drawbacks are associated with the use of these drugs, including toxicity, poor oral bioavailability (except VGCV), and emergence of drug resistance (3,20). The active forms of GCV, CDF, and FOS share the same molecular target, the viral polymerase UL54. Consequently, drug-resistant strains of HCMV encoding UL54 mutations have been found for all three compounds, and the emergence of cross-resistant strains has been described in clinical settings. In addition, resistance to GCV is also associate...

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Section: Discussionmentioning

confidence: 99%

In Vitro and In Vivo Activities of the Novel Anticytomegalovirus Compound AIC246

Lischka

Hewlett

Wunberg

et al. 2010

Antimicrob Agents Chemother

222

179

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“…The effect of mycophenolate mofetil on the development of Tregs is controversial. 16,17,31 Treg numbers are increased after treatment with a combination of mycophenolate mofetil and vitamin D3. 17 However, other experimental studies have not demonstrated relevant negative effects of mycophenolate mofetil on the development and function of Tregs.…”

Section: Discussionmentioning

confidence: 99%

“…17 However, other experimental studies have not demonstrated relevant negative effects of mycophenolate mofetil on the development and function of Tregs. 31 Furthermore, an experimental mouse study showed that mycophenolate mofetil at therapeutic doses may exert an inhibitory effect on Treg proliferation and function. 16 In the current study, analysis of splenic tissue did not reveal significant differences in Treg counts between the different experimental groups.…”

Section: Discussionmentioning

confidence: 99%

Reduction of Transplant Arteriosclerosis After Treatment With Mycophenolate Mofetil and Ganciclovir in a Mouse Aortic Allograft Model

Hoffmann¹,

Böhm²,

Abele-Ohl³

et al. 2012

Exp Clin Transplant

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Objectives: Transplant arteriosclerosis is a major obstacle for long-term allograft survival in heart transplant. The aim of this study was to investigate potential synergistic effects of combined treatment with mycophenolate mofetil and ganciclovir on the development of transplant arteriosclerosis, presence of regulatory T cells, and expression of donor specific alloantibodies. Materials and Methods: Donor aortas from C57BL/6 (H2b) mice that were fully mismatched to the major histocompatibility complex were transplanted into CBA (H2k) mouse recipients. Groups of mice received mycophenolate mofetil (100 or 300 mg/kg, oral), ganciclovir (10 or 72 mg/kg, intraperitoneal), or a mycophenolate mofetil and ganciclovir combination. Grafts were analyzed by histology and morphometry on day 30 after transplant. Numbers of regulatory T cells and donor-specific alloantibodies were examined by fluorescenceactivated cell sorting analysis of splenic tissue and peripheral blood. Results: Mycophenolate mofetil (100 mg/kg) and ganciclovir (10 mg/kg and 72 mg/kg) did not show effects on transplant arteriosclerosis formation or alloantibody production. However, groups treated with mycophenolate mofetil (300 mg/kg) or a lowor high-dose mycophenolate mofetil and ganciclovir combination had significantly reduced transplant arteriosclerosis and alloantibody levels. Expression of regulatory T cells within the spleen was similar between all experimental groups and untreated controls. Conclusions: The combination of mycophenolate mofetil and ganciclovir significantly reduced the development of transplant arteriosclerosis in a mouse abdominal aortic allograft model. This effect may be a result of decreased alloantibody production.

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“…However, the hu-SCID mouse model is difficult to work with and there is potential for variation between labs. A recent innovation of this approach is the use of an artificial surgical gel foam matrix containing HCMV infected human fibroblast cells, which is surgically embedded in the SCID mouse [135]. Potentially, this approach could standardize the model and allow the testing of different human cell lineages and HCMV antiviral therapies.…”

Section: CMV Antivirals and Animal Modelsmentioning

confidence: 99%

Cytomegalovirus antivirals and development of improved animal models

McGregor

Choi

2011

Expert Opinion on Drug Metabolism & Toxicology

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Introduction Cytomegalovirus (CMV) is a ubiquitous pathogen that establishes a life long asymptomatic infection in healthy individuals. Infection of immunesuppressed individuals causes serious illness. Transplant and AIDS patients are highly susceptible to CMV leading to life threatening end organ disease. Another vulnerable population is the developing fetus in utero, where congenital infection can result in surviving newborns with long term developmental problems. There is no vaccine licensed for CMV and current antivirals suffer from complications associated with prolonged treatment. These include drug toxicity and emergence of resistant strains. There is an obvious need for new antivirals. Candidate intervention strategies are tested in controlled pre-clinical animal models but species specificity of HCMV precludes the direct study of the virus in an animal model. Areas covered This review explores the current status of CMV antivirals and development of new drugs. This includes the use of animal models and the development of new improved models such as humanized animal CMV and bioluminescent imaging of virus in animals in real time. Expert Opinion Various new CMV antivirals are in development, some with greater spectrum of activity against other viruses. Although the greatest need is in the setting of transplant patients there remains an unmet need for a safe antiviral strategy against congenital CMV. This is especially important since an effective CMV vaccine remains an elusive goal. In this capacity greater emphasis should be placed on suitable pre-clinical animal models and greater collaboration between industry and academia.

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A model of human cytomegalovirus infection in severe combined immunodeficient mice

Cited by 18 publications

References 25 publications

In Vitro and In Vivo Activities of the Novel Anticytomegalovirus Compound AIC246

In Vitro and In Vivo Activities of the Novel Anticytomegalovirus Compound AIC246

Reduction of Transplant Arteriosclerosis After Treatment With Mycophenolate Mofetil and Ganciclovir in a Mouse Aortic Allograft Model

Cytomegalovirus antivirals and development of improved animal models

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