Viral Bcl-2-mediated evasion of autophagy aids chronic infection of gammaherpesvirus 68.
Gamma-herpesviruses (gammaHVs) have developed an interaction with their hosts wherein they establish a life-long persistent infection and are associated with the onset of various malignancies. One critical virulence factor involved in the persistency of murine gamma-herpesvirus 68 (gammaHV68) is the viral homolog of the Bcl-2 protein (vBcl-2), which has been implicated to counteract both host apoptotic responses and autophagy pathway. However, the relative significance of the two activities of vBcl-2 in viral persistent infection has yet to be elucidated. Here, by characterizing a series of loss-of-function mutants of vBcl-2, we have distinguished the vBcl-2-mediated antagonism of autophagy from the vBcl-2-mediated inhibition of apoptosis in vitro and in vivo. A mutant gammaHV68 virus lacking the anti-autophagic activity of vBcl-2 demonstrates an impaired ability to maintain chronic infections in mice, whereas a mutant virus lacking the anti-apoptotic activity of vBcl-2 establishes chronic infections as efficiently as the wild-type virus but displays a compromised ability for ex vivo reactivation. Thus, the vBcl-2-mediated antagonism of host autophagy constitutes a novel mechanism by which gammaHVs confer persistent infections, further underscoring the importance of autophagy as a critical host determinant in the in vivo latency of gamma-herpesviruses.
E
Xiaofei
X
Department of Microbiology and Molecular Genetics and Tumor Virology Division, New England Primate Research Center, Harvard Medical School, Southborough, Massachusetts, United States of America.
Hwang
Seungmin
S
Oh
Soohwan
S
Lee
Jong-Soo
JS
Jeong
Joseph H
JH
Gwack
Yousang
Y
Kowalik
Timothy F
TF
Sun
Ren
R
Jung
Jae U
JU
Liang
Chengyu
C
D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D001343:Autophagy / Q000235:genetics / Q000276:immunology; D000071186:Beclin-1; D018142:Gammaherpesvirinae / Q000235:genetics* / Q000276:immunology / Q000502:physiology; D016147:Genes, Tumor Suppressor; D006566:Herpesviridae Infections / Q000473:pathology; D008247:Lysosomes / Q000821:virology; D051379:Mice; D009154:Mutation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics*; D018144:Rhadinovirus / Q000235:genetics / Q000276:immunology / Q000502:physiology; D014774:Virulence
D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; C115010:Becn1 protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2