Viral cyclins mediate separate phases of infection by integrating functions of distinct mammalian cyclins.
Gammaherpesvirus cyclins have expanded biochemical features relative to mammalian cyclins, and promote infection and pathogenesis including acute lung infection, viral persistence, and reactivation from latency. To define the essential features of the viral cyclin, we generated a panel of knock-in viruses expressing various viral or mammalian cyclins from the murine gammaherpesvirus 68 cyclin locus. Viral cyclins of both gammaherpesvirus 68 and Kaposi's sarcoma-associated herpesvirus supported all cyclin-dependent stages of infection, indicating functional conservation. Although mammalian cyclins could not restore lung replication, they did promote viral persistence and reactivation. Strikingly, distinct and non-overlapping mammalian cyclins complemented persistence (cyclin A, E) or reactivation from latency (cyclin D3). Based on these data, unique biochemical features of viral cyclins (e.g. enhanced kinase activation) are not essential to mediate specific processes during infection. What is essential for, and unique to, the viral cyclins is the integration of the activities of several different mammalian cyclins, which allows viral cyclins to mediate multiple, discrete stages of infection. These studies also demonstrated that closely related stages of infection, that are cyclin-dependent, are in fact genetically distinct, and thus predict that cyclin requirements may be used to tailor potential therapies for virus-associated diseases.
Department of Microbiology, University of Colorado Denver, Anschutz Medical Campus, Aurora, Colorado, USA.
Katherine S
KS
Lee
Andrea L
AL
Suarez
David J
DJ
Claypool
Taylor K
TK
Armstrong
Erin M
EM
Buckingham
Linda F
LF
van Dyk
D000818:Animals; D016213:Cyclins / Q000235:genetics / Q000378:metabolism*; D018142:Gammaherpesvirinae / Q000235:genetics* / Q000378:metabolism / Q000472:pathogenicity* / Q000502:physiology; D015967:Gene Expression Regulation, Viral; D006566:Herpesviridae Infections / Q000235:genetics / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*; D014775:Virus Activation / Q000235:genetics; D014779:Virus Replication / Q000235:genetics
D016213:Cyclins; D014764:Viral Proteins