Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2006 Jan;80(1):192-200.
doi: 10.1128/JVI.80.1.192-200.2006.

Gamma interferon blocks gammaherpesvirus reactivation from latency

Ashley L Steed  1 , Erik S Barton, Scott A Tibbetts, Daniel L Popkin, Mary L Lutzke, Rosemary Rochford, Herbert W Virgin 4th
Affiliations

Gamma interferon blocks gammaherpesvirus reactivation from latency

Ashley L Steed et al. J Virol. 2006 Jan.

Abstract

Establishment of latent infection and reactivation from latency are critical aspects of herpesvirus infection and pathogenesis. Interfering with either of these steps in the herpesvirus life cycle may offer a novel strategy for controlling herpesvirus infection and associated disease pathogenesis. Prior studies show that mice deficient in gamma interferon (IFN-gamma) or the IFN-gamma receptor have elevated numbers of cells reactivating from murine gammaherpesvirus 68 (gammaHV68) latency, produce infectious virus after the establishment of latency, and develop large-vessel vasculitis. Here, we demonstrate that IFN-gamma is a powerful inhibitor of reactivation of gammaHV68 from latency in tissue culture. In vivo, IFN-gamma controls viral gene expression during latency. Importantly, depletion of IFN-gamma in latently infected mice results in an increased frequency of cells reactivating virus. This demonstrates that IFN-gamma is important for immune surveillance that limits reactivation of gammaHV68 from latency.

PubMed Disclaimer

Figures

FIG. 1.
FIG. 1.
IFN-γ controls the frequency of peritoneal cells that reactivate from γHV68 latency. (A) Ex vivo reactivation. The statistical differences between medium and 1 U/ml, medium and 10 U/ml, and medium and 100 U/ml of IFN-γ are P = 0.002, P < 0.0001, and P < 0.0001, respectively. (B) IFN-γ does not affect the ability of γHV68 to cause CPE on the MEF monolayer. (C) IFN-γ does not activate peritoneal cells such that the ability of γHV68 to cause CPE on the MEF monolayer is altered. n, number of independent experiments.
FIG. 2.
FIG. 2.
IFN-γ-mediated inhibition of γHV68 reactivation is neutralizable by anti-IFN-γ antibody early after explantation. Ex vivo reactivation is shown. The statistical difference between medium and plates with 10 U of IFN-γ/ml is P < 0.0001. PIP-treated plates were not statistically different from IFN-γ plates on any day. H22-treated plates were statistically different from IFN-γ plates at days 1, 2, 3, and 5 with the following P values: P = 0.03, P = 0.04, P = 0.05, and P = 0.05, respectively. At day 4, the difference between H22-treated plates and IFN-γ plates was not significant (P = 0.07). The capacity of neutralizing antibody to inhibit reactivation waned over time. By day 8, the ability to neutralize IFN-γ with H22 was lost. the statistical difference between day 1 H22-treated plates and day 8 H22-treated plates was significant at P = 0.01. n, number of independent experiments.
FIG. 3.
FIG. 3.
IFN-γ-mediated inhibition of γHV68 reactivation acts during viral reactivation ex vivo. (A) Ex vivo reactivation stopped at various days by three freeze-thaw cycles. The statistical significance of the difference between unfrozen and frozen results on day 0, day 2, and day 4 is P = 0.015. (B) Ex vivo reactivation after addition of IFN-γ at various days. The statistical significance of the difference between medium and day 0, day 1, and day 2 is P = 0.001, P = 0.02, P = 0.04, respectively. n, number of independent experiments.
FIG. 4.
FIG. 4.
IFN-γ inhibits reactivation from latency through the IFN-γ receptor. (A) Ex vivo reactivation. At 28 days postinfection, peritoneal cells from IFN-γR−/− mice were harvested and assayed for frequency of reactivation by limiting dilution in the presence or absence of 100 U of IFN-γ/ml. Parallel samples were mechanically disrupted (dis.) to determine the presence of persistent virus at the time of plating. n, number of independent experiments.
FIG. 5.
FIG. 5.
IFN-γ does not suppress reactivation of γHV68 through a paracrine effect on infected cells. Ex vivo reactivation is shown. The numbers in the legend indicate the ratios in which the wild-type peritoneal cells were mixed with the IFN-γR−/− peritoneal cells. The concentration of IFN-γ used was 100 U/ml. The statistical significance of the difference between wild-type cells plated in the presence and absence of IFN-γ was P = 0.02.
FIG. 6.
FIG. 6.
Peritoneal cells from chronically infected IFN-γR−/− mice have a different profile of viral gene expression than peritoneal cells from wild-type mice. (A) RNase protection assay. RNA was isolated from peritoneal cells of infected wild-type or IFN-γR−/− mice and analyzed by RPA for expression of γHV68 genes. RNA from three mice (lanes A, B, and C) were analyzed for each group. The positive control is RNA extracted from infected OMK cells. Shown is a representative phosphorimage from three experiments. (B) Phosphorimager quantitation for viral mRNAs and host mRNA L32.
FIG. 7.
FIG. 7.
In vivo depletion of IFN-γ after the establishment of latency leads to an increase in the frequency of cells reactivating from latency. (A) Ex vivo reactivation. The difference in these reactivation curves is statistically significant (P = 0.003). (B) Frequency of genome-bearing cells. n, number of independent experiments.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Alber, D. G., K. L. Powell, P. Vallance, D. A. Goodwin, and C. Grahame-Clarke. 2000. Herpesvirus infection accelerates atherosclerosis in the apolipoprotein E-deficient mouse. Circulation 102:779-785. - PubMed
    1. Bancroft, G. J., R. D. Schreiber, G. C. Bosma, M. J. Bosma, and E. R. Unanue. 1987. A T cell-independent mechanism of macrophage activation by interferon-gamma. J. Immunol. 139:1104-1107. - PubMed
    1. Boehm, U., T. Klamp, M. Groot, and J. C. Howard. 1997. Cellular responses to interferon-gamma. Annu. Rev. Immunol. 15:749-795. - PubMed
    1. Cardin, R. D., J. W. Brooks, S. R. Sarawar, and P. C. Doherty. 1996. Progressive loss of CD8+ T cell-mediated control of a gamma-herpesvirus in the absence of CD4+ T cells. J. Exp. Med. 184:863-871. - PMC - PubMed
    1. Chang, Y., E. Cesarman, M. S. Pessin, F. Lee, J. Culpepper, D. M. Knowles, and P. S. Moore. 1994. Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma. Science 266:1865-1869. - PubMed

Publication types

MeSH terms

LinkOut - more resources