Efficacy of acyclovir against mouse cytomegalovirus in vivo

Wingard, John R.; Bender, William J.; Saral, Rein; Burns, William H.

doi:10.1128/aac.20.2.275

Cited by 13 publications

(3 citation statements)

References 18 publications

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“…While lethal MCMV disease in immunocompetent BALB/c mice is attributed to liver damage culminating in a severe hepatitis within the first week of infection (69), factors contributing to this disease have not been characterized. Disease is prevented by administration of antiviral drugs, revealing a critical contribution of ongoing viral replication (81). Unlike other forms of hepatitis, tumor necrosis factor (TNF) is dispensable for disease in BALB/c mice (70).…”

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Antiviral T Cell Response Triggers Cytomegalovirus Hepatitis in Mice

Livingston-Rosanoff

Daley‐Bauer

García

et al. 2012

J Virol

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e One common sign of human cytomegalovirus infection is altered liver function. Murine cytomegalovirus strain v70 induces a rapid and severe hepatitis in immunocompetent mice that requires the presence of T cells in order to develop. v70 exhibits approximately 10-fold-greater virulence than the commonly used strain K181, resulting in a more severe, sustained, and lethal hepatitis but not dramatically higher viral replication levels. Hepatitis and death are markedly delayed in immunodeficient SCID compared to immunocompetent BALB/c mice. Transfer of BALB/c splenocytes to SCID mice conferred rapid disease following infection, and depletion of either CD4 or CD8 T cells in BALB/c mice reduced virus-induced hepatitis. The frequency of CD8 T cells producing gamma interferon and tumor necrosis factor in response to viral antigen was higher in settings where more severe disease occurred. Thus, virus-specific effector CD8 T cells appear to contribute to lethal virus-induced hepatitis, contrasting their protective role during sublethal infection. This study reveals how protection and disease during cytomegalovirus infection depend on viral strain and dose, as well as the quality of the T cell response.

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Antiviral T Cell Response Triggers Cytomegalovirus Hepatitis in Mice

Livingston-Rosanoff

Daley‐Bauer

García

et al. 2012

J Virol

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“…Because the viral TK appeared to be necessary for the phosphorylation of ACV leading to accumulation of acyclo-GTP in infected cells and expression of its anti-HSV effect, it was not surprising to find that human cytomegalovirus, a herpesvirus that does not encode for a TK, is much less sensitive to ACV (7). In contrast, the finding that mouse cytomegalovirus (MCMV), another herpesvirus lacking a TK (10, 21), is almost as sensitive to ACV in vitro and in vivo as is HSV was unexpected (2,28). Even when grown in TK-negative host cells, the replication of MCMV is sensitive to ACV, indicating a mechanism not dependent on cellular or viral TK for converting ACV to its active form (2).…”

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Genetic analysis of the susceptibility of mouse cytomegalovirus to acyclovir

Sandford¹,

Wingard²,

Simons³

et al. 1985

J Virol

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Eight independently derived mouse cytomegalovirus (MCMV) mutants resistant to acyclovir (ACV) were obtained by the sequential plating of wild-type virus in increasing concentrations of ACV. Results of complementation studies among these eight mutants suggest that all had mutations within the same or closely associated genes. A ninth MCMV mutant resistant to phosphonoacetate (PAA) derived by plating wild-type virus in the presence of 100 ,ug of PAA per ml displayed coresistance to ACV and was unable to complement any of the ACV-derived mutants. Recombination experiments among all combinations of the nine MCMV mutants were performed and supported the complementation data in that no recombination could be detected. Seven of the eight ACV-resistant mutants demonstrated cross-resistance to PAA and hypersensitivity to aphidicolin. The one mutant not coresistant to PAA was more susceptible to PAA than was the parent virus. Only a few mutants demonstrated coresistance when the mutants were tested against 9-jI-Darabinofuranosyladenine (ara-A). The ACV mutant that demonstrated increased susceptibility to PAA was 30-fold more susceptible to ara-A but remained unchanged in susceptibility to aphidicolin. Two of the parent-mutant combinations were selected for DNA synthesis analysis in the presence of ACV (5 jiM). A significant decrease in DNA synthesis was demonstrated for both parent viruses, and there was little effect on mutant virus DNA synthesis at the same drug concentration. These results suggest that susceptibility of MCMV to ACV is confined to a product of a single gene and that a mutation of this gene can lead to an altered phenotype when compared with parent virus in susceptibility of DNA synthesis to PAA, ara-A, and aphidicolin, drugs that are known to inhibit DNA polymerase activity.

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“…However, administration of a single dose of cyclophosphamide (CP) 24 h after virus inoculation induced diffuse interstitial pneumonitis not seen with either virus or CP alone (9). In the studies reported here, we compared the effects of ACV with those of another related antiviral purine analog, 9-(1,3-dihydroxy-2-propoxymethyl)guanine (DHPG), on MCMV replication in lung tissues and on the evolution of interstitial pneumonitis after administration of virus and CP (1,2,7,12). In addition, we compared the antiviral activities of these two compounds on MCMV replication in vitro.…”

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Inhibition of murine cytomegalovirus lung infection and interstitial pneumonitis by acyclovir and 9-(1,3-dihydroxy-2-propoxymethyl)guanine

Shanley¹,

Morningstar²,

Jordan³

1985

Antimicrob Agents Chemother

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We compared the effects of acyclovir (ACV) and 9-(1,3-dihydroxy-2-propoxymethyl)guanine (DHPG) on murine cytomegalovirus (MCMV) replication in lung and salivary gland tissues, the evolution of interstitial pneumonitis in vivo, and MCMV replication in mouse embryo cells in vitro. As measured by plaque reduction, ACV was more active than DHPG in vitro. In vivo, whether administered orally by gastric intubation or in the drinking water, or subcutaneously, DHPG was more effective than ACV in reducing MCMV titers in lung or salivary gland tissues. This was true in both normal and cyclophosphamide-treated mice. Neither drug was able to prevent MCMV interstitial pneumonitis, despite substantial reductions in virus titer, but both drugs reduced the severity of the pneumonitis.Lung infection and interstitial pneumonitis due to cytomegalovirus (CMV) constitute common and often lifethreatening problems for individuals whose immune defenses have been altered by disease or medical therapy (3). The pathogenetic mechanisms leading to CMV lung infection and interstitial pneumonitis are poorly understood. However, the advent of successful antiviral chemotherapy for other herpesvirus infections has prompted a search for therapeutic modalities which might improve the prospects of individuals with pulmonary involvement due to CMV. At present, the available shemotherapeutic agents have poor in vitro antiviral activity against most strains of CMV, and uncontrolled therapeutic trials of agents such as interferon, acyclovir (ACV), and vidarabine against CMV interstitial pneumonitis have been disappointing (4,5,10,11). The search for more effective antiviral agents for the treatment of CMV interstitial pneumonitis is an area of intense interest.We have been studying a model of murine CMV (MCMV) lung infection to better define the roles of host and viral factors in the genesis of MCMV interstitial pneumonitis (8, 9). In BALB/c mice inoculated intranasally with MCMV,

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Efficacy of acyclovir against mouse cytomegalovirus in vivo

Cited by 13 publications

References 18 publications

Antiviral T Cell Response Triggers Cytomegalovirus Hepatitis in Mice

Antiviral T Cell Response Triggers Cytomegalovirus Hepatitis in Mice

Genetic analysis of the susceptibility of mouse cytomegalovirus to acyclovir

Inhibition of murine cytomegalovirus lung infection and interstitial pneumonitis by acyclovir and 9-(1,3-dihydroxy-2-propoxymethyl)guanine

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