Dose and duration-dependence of ganciclovir treatment against murine cytomegalovirus infection in severe combined immunodeficient mice

Duan, Jianmin; Paris, William; Kibler, Philip; Bousquet, Christiane; Liuzzi, Michel; Cordingley, Michael G.

doi:10.1016/s0166-3542(98)00038-2

Cited by 16 publications

(9 citation statements)

References 22 publications

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“…Members of our group and others have used SCID mice inoculated with MCMV as a model for CMV infection in the murine compromised host (13,19,30,42,45). Since SCID mice are profoundly immunocompromised, approximately 1 to 3 PFU will result in a lethal infection.…”

Section: Discussionmentioning

confidence: 99%

Oral Activity of a Methylenecyclopropane Analog, Cyclopropavir, in Animal Models for Cytomegalovirus Infections

Kern

Bidanset

Hartline

et al. 2004

Antimicrob Agents Chemother

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We reported previously that purine 2-(hydroxymethyl)methylenecyclopropane analogs have good activity against cytomegalovirus infection. A second-generation analog, (Z)-9-{[2,2-bis-(hydroxymethyl)cyclopropylidene] methyl}guanine (ZSM-I-62, cyclopropavir [CPV]), has particularly good activity against murine and human cytomegaloviruses (MCMV and HCMV) in vitro. To determine the oral activity of this compound in vivo, BALB/c or severe combined immunodeficient (SCID) mice infected with MCMV and two models using SCID mice implanted with human fetal tissue and subsequently infected with HCMV were used. In MCMV-infected normal mice, CPV at 10 mg/kg of body weight was highly effective in preventing mortality when administered at 24, 48, or 72 h post-viral inoculation and reduced titers of virus in tissues of SCID mice by 2 to 5 log 10 . In one HCMV model, human fetal retinal tissue was implanted into the anterior chamber of the mouse eye and inoculated with the Toledo strain of HCMV, and in the second, human fetal thymus and liver tissues were implanted under the kidney capsule of mice and then inoculated with HCMV. In general, replication of HCMV in both types of implant tissue increased from 7 through 21 to 28 days and then gradually decreased to undetectable levels by 8 weeks postinfection. Oral treatment with 45 or 15 mg of CPV/kg initiated 24 h after infection was highly effective in reducing replication to undetectable levels in both models and was generally more effective than ganciclovir. These data indicate that the methylenecyclopropane analog, CPV, was highly efficacious in these four animal models and should be evaluated for use in HCMV infections in humans.

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Section: Discussionmentioning

confidence: 99%

Oral Activity of a Methylenecyclopropane Analog, Cyclopropavir, in Animal Models for Cytomegalovirus Infections

Kern

Bidanset

Hartline

et al. 2004

Antimicrob Agents Chemother

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“…This lack of difference is most likely due to the short postinoculation experimental duration of less than a week, a period dictated by the high neonatal mortality rate during a longer postinoculation interval. Compared to normal controls, a substantially greater degree of CMV infection is found in the peripheral organs and retinas of SCID mice when they were maintained for a long survival time; SCID mice also show a higher degree of mortality from CMV infections (1,15,29,35). After peripheral CMV infection, we find no difference in CNS infection between SCID and controls after a week, but at longer intervals we find a high degree of infection in SCID, but not control, mouse brains (Reuter et al, Abstr.…”

Section: Discussionmentioning

confidence: 99%

Enhanced Cytomegalovirus Infection of Developing Brain Independent of the Adaptive Immune System

Pol¹,

Reuter

Santarelli³

2002

J Virol

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Cytomegalovirus (CMV) has been suggested as the most prevalent infectious agent causing neurological dysfunction in the developing brain; in contrast, CMV infections are rare in the adult brain. One explanation generally given for the developmental susceptibility to the virus is that the developing immune system is too immature to protect the central nervous system from viral infection, but as the immune system develops it can protect the brain. We suggest an alternate view: that developing brain cells are inherently more susceptible to CMV infection, independent of the immune system. We used a recombinant mouse CMV that leads to green fluorescent protein expression in infected cells. Control experiments demonstrated a high correlation between the number of cells detected with the viral GFP reporter gene and with immunocytochemical detection of the virus. After intracerebral inoculation, the number of CMV-infected cells in neonatal brains was many times greater than in mature control or mature immunodepressed SCID mice, and the mortality rate of neonates was substantially greater than SCID or control adults. Parallel experiments with live brain slices inoculated in vitro, done in the absence of the systemic immune system, generated similar data, with immature hippocampus, hypothalamus, cortex, striatum, and cerebellum showing substantially greater numbers of infected cells (100-fold) than found in adult slices in these same regions. Interestingly, in the cerebellar cortex, CMV-infected cells were more prevalent in the postmitotic Purkinje cell layer than in the mitotic granule cell layer, suggesting a selective infection of some cell types not dependent on cell division. Together, these data support the view that CMV has an intrinsic preference for infection of developing brain cells, independent, but not mutually exclusive, of the developmental status of the systemic immune system in controlling CMV infection.Cytomegalovirus (CMV) has been suggested as the leading viral cause of birth defects and neurological dysfunction (3,47). Infections of the developing brain can lead to a number of problems, including mental retardation, epilepsy, microencephaly, microgyria, hydrocephalus, and deafness (4, 20, 33). The incidence of CMV-induced neurological problems has been estimated at 0.1% of births, with a possibility of moresubtle problems, such as learning deficits, in infected children (20,23). In contrast to the susceptibility of the developing central nervous system (CNS), CMV is not a particular threat to the mature brain, except under conditions of a compromised immune system (21,30).CMV causes a number of cellular problems, including cytomegaly and syncytium formation, leading to cell death or viral latency. CMV shows substantial species specificity, replicating selectively in the host species. Mouse and human CMV each have genomes of 235 kb of double-stranded DNA, have similar tissue affinity, similar viral morphology and biology, similar ability to achieve long-term latency, and colinear gene sequences with di...

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“…Ganciclovir dosing of 10mg/kg/day (in 0.2 cc saline vehicle) was chosen because this has been shown to be efficacious in mice [23,24]. This is also a standard dose in adults for CMV disease.…”

Section: Reactivationmentioning

confidence: 99%

Pulmonary cytomegalovirus reactivation causes pathology in immunocompetent mice*

Cook

Zhang

Sedmak

et al. 2006

Critical Care Medicine

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Introduction-Cytomegalovirus (CMV) is a ubiquitous herpes virus that persists in the host in a latent state following primary infection. We have recently observed that CMV reactivates in lungs of critically ill surgical patients, and that this reactivation can be triggered by bacterial sepsis. Although CMV is a known pathogen in immunosuppressed transplant patients, it is unknown whether reactivated CMV is a pathogen in immunocompetent hosts. Using an animal model of latency/ reactivation, we studied the pathobiology of CMV reactivation in the immunocompetent host.

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Dose and duration-dependence of ganciclovir treatment against murine cytomegalovirus infection in severe combined immunodeficient mice

Cited by 16 publications

References 22 publications

Oral Activity of a Methylenecyclopropane Analog, Cyclopropavir, in Animal Models for Cytomegalovirus Infections

Oral Activity of a Methylenecyclopropane Analog, Cyclopropavir, in Animal Models for Cytomegalovirus Infections

Enhanced Cytomegalovirus Infection of Developing Brain Independent of the Adaptive Immune System

Pulmonary cytomegalovirus reactivation causes pathology in immunocompetent mice*

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