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. 2000 Dec;74(23):11304-10.
doi: 10.1128/jvi.74.23.11304-11310.2000.

Ongoing viral replication is required for gammaherpesvirus 68-induced vascular damage

A J Dal Canto  1 , H W Virgin 4th, S H Speck
Affiliations

Ongoing viral replication is required for gammaherpesvirus 68-induced vascular damage

A J Dal Canto et al. J Virol. 2000 Dec.

Abstract

The role of autoimmunity in large-vessel vasculitis in humans remains unclear. We have previously shown that infection of gamma interferon receptor knockout (IFN-gamma R(-/-)) mice with gammaherpesvirus 68 (gamma HV68) results in severe inflammation of the large elastic arteries that is pathologically similar to the lesions observed in Takayasu's arteritis, the nongranulomatous variant of temporal arteritis, and Kawasaki's disease (K. E. Weck et al., Nat. Med. 3:1346-1353, 1997). Here we define the mechanism of damage to the elastic arteries. We show that there is a persistent productive infection of the media of the large elastic vessels. In addition, we demonstrate that persistent virus replication is necessary for chronic arteritis, since antiviral therapy of mice with established disease resulted in increased survival, clearance of viral antigen from the media of the affected vessel, and dramatic amelioration of arteritic lesions. These data argue that ongoing virus replication, rather than autoimmunity, is the cause of gamma HV68-induced elastic arteritis.

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Figures

FIG. 1
FIG. 1
Chronic productive γHV68 infection in the arteritic media. (A through C) Serial sections from an arteritic lesion in a γHV68-infected IFN-γR−/− mouse that was sacrificed 11 weeks p.i. Adv, adventitia; M, media; I, intima; L, lumen. (A) H&E-stained section. (B) DNA in situ hybridization with a γHV68-specific DNA probe. Dark staining within the media represents specific signal. (C) DNA in situ hybridization with an MCMV-specific DNA probe. Light blue staining in the lumen with both γHV68 and MCMV DNA probes represents background staining from the glass slide. (D) Electron micrograph of the media of an arteritic lesion from an IFN-γR−/− mouse that died 6 weeks p.i. Black arrows indicate extracellular mature virions. White arrows indicate virions in the cytoplasm of a smooth muscle cell (SMC). EL, elastic lamina; SMC, smooth muscle cell. Magnification, ×11,500. (E) Enlargement of region containing extracellular virions from the electron micrograph shown in panel D. (F) Enlargement of region containing cytoplasmic virions from the electron micrograph shown in panel D.
FIG. 2
FIG. 2
Cidofovir treatment of γHV68-infected SCID mice. Mice were infected with 1,000 PFU of γHV68. Mice were either left untreated or given subcutaneous injections of the antiviral drug cidofovir (25 mg/kg) beginning at day 1 postinfection, as indicated. All treatments consisted of a 2-day loading dose (days 1 and 2 postinfection) followed by the indicated schedules. Data are means ± standard errors of the means for 3 to 4 mice per group in a single experiment. Mice were sacrificed 10 days postinfection, and splenic viral titers were determined.
FIG. 3
FIG. 3
Cidofovir increases the survival of γHV68-infected IFN-γR−/− mice infected with 4 × 107 PFU of virus. Antiviral therapy was initiated 24 days postinfection, at which time a group of 18 mice were sacrificed; 15 of these (83%) had arteritis. Each point represents an event (death or sacrifice). The arrow indicates the day on which antiviral therapy was initiated. Asterisks represent the time points at which mice were sacrificed. P = 0.0003 for the survival advantage of cidofovir-treated mice over PBS-treated controls.
FIG. 4
FIG. 4
Representative aortic lesions and scores from control and cidofovir-treated mice. γHV68-infected IFN-γR−/− mice were treated with either PBS or cidofovir beginning at 24 days postinfection, as described in Materials and Methods. (A) Lesion with a score of 5 from a PBS-treated control mouse that died 6 weeks postinfection. (B) Representative lesion with a score of 2 from a cidofovir-treated mouse that was sacrificed after 8.5 weeks of therapy. (C and D) Representative lesions with scores of 1 from cidofovir-treated mice that were sacrificed after 8.5 weeks of therapy. Note the noninflammatory intimal thickening in panels B, C, and D. Adv, adventitia; M, media; I, intima; L, lumen.
FIG. 5
FIG. 5
Cidofovir treatment leads to clearance of γHV68 antigen and amelioration of pathology. Shown is a plot of lesion severity scores, as described in Table 1, as a function of time of death or sacrifice. Only mice with lesions are represented. The presence or absence of viral antigen (Ag) in lesions was assessed by immunohistochemistry as described in Materials and Methods (Ag staining). Weeks p.i., time postinfection of death or sacrifice. Since there were no differences in lesion severity for viral antigen-positive lesions of mice that died or were sacrificed 4 to 8 weeks postinfection, these data were pooled in columns 1 and 2. Mice in columns 3, 4, and 5 were all sacrificed. ∗, P < 0.0001 compared to scores for PBS-treated mice. ∗∗, P = 0.01 compared to scores in column 3.
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