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Journal of Virology, July 2009, p. 6883-6899, Vol. 83, No. 13
0022-538X/09/$08.00+0     doi:10.1128/JVI.00245-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Activation of the PI3K/Akt Pathway Early during Vaccinia and Cowpox Virus Infections Is Required for both Host Survival and Viral Replication{triangledown}

Jamária A. P. Soares,1,2,{dagger},{ddagger} Flávia G. G. Leite,1,2,{dagger} Luciana G. Andrade,1,2 Alice A. Torres,1,2 Lirlândia P. De Sousa,3,4 Lucíola S. Barcelos,4,5 Mauro M. Teixeira,4 Paulo C. P. Ferreira,2 Erna G. Kroon,2 Thaís Souto-Padrón,6 and Cláudio A. Bonjardim1,2*

Grupo de Transdução de Sinal,1 Laboratório de Vírus,2 Departamento de Microbiologia, Setor de Patologia, Coltec/UFMG,3 Laboratório de Imunofarmacologia, Departamento de Bioquímica e Imunologia,4 Departamento de Fisiologia e Biofísica, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, 31270-901 Belo Horizonte, Minas Gerais,5 Laboratório de Biologia Celular e Ultraestrutura, Universidade Federal do Rio de Janeiro, 21941-590 Rio de Janeiro, Brazil6

Received 4 February 2009/ Accepted 13 April 2009

Viral manipulation of the transduction pathways associated with key cellular functions such as actin remodeling, microtubule stabilization, and survival may favor a productive viral infection. Here we show that consistent with the vaccinia virus (VACV) and cowpox virus (CPXV) requirement for cytoskeleton alterations early during the infection cycle, PBK/Akt was phosphorylated at S473 [Akt(S473-P)], a modification associated with the mammalian target of rapamycin complex 2 (mTORC2), which was paralleled by phosphorylation at T308 [Akt(T308-P)] by PI3K/PDK1, which is required for host survival. Notably, while VACV stimulated Akt(S473-P/T308-P) at early (1 h postinfection [p.i.]) and late (24 h p.i.) times during the infective cycle, CPXV stimulated Akt at early times only. Pharmacological and genetic inhibition of PI3K (LY294002) or Akt (Akt-X and a dominant-negative form of Akt-K179M) resulted in a significant decline in virus yield (from 80% to ≥90%). This decline was secondary to the inhibition of late viral gene expression, which in turn led to an arrest of virion morphogenesis at the immature-virion stage of the viral growth cycle. Furthermore, the cleavage of both caspase-3 and poly(ADP-ribose) polymerase and terminal deoxynucleotidyl transferase-mediated deoxyuridine nick end labeling assays confirmed that permissive, spontaneously immortalized cells such as A31 cells and mouse embryonic fibroblasts (MEFs) underwent apoptosis upon orthopoxvirus infection plus LY294002 treatment. Thus, in A31 cells and MEFs, early viral receptor-mediated signals transmitted via the PI3K/Akt pathway are required and precede the expression of viral antiapoptotic genes. Additionally, the inhibition of these signals resulted in the apoptosis of the infected cells and a significant decline in viral titers.

* Corresponding author. Mailing address: Grupo de Transdução de Sinal, Laboratório de Vírus, Departamento de Microbiologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Av. Antônio Carlos, 6627 Campus Pampulha, 31270-901 Belo Horizonte, Minas Gerais, Brazil. Phone: 55-31 3409-2752. Fax: 55-31 3443-6482. E-mail: claudio.bonjardim{at}gmail.com

{triangledown} Published ahead of print on 22 April 2009.

{dagger} J.A.P.S. and F.G.G.L. contributed equally to this work.

{ddagger} Present address: Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, WI.

Journal of Virology, July 2009, p. 6883-6899, Vol. 83, No. 13
0022-538X/09/$08.00+0     doi:10.1128/JVI.00245-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Dunn, E. F., Fearns, R., Connor, J. H. (2009). Akt Inhibitor Akt-IV Blocks Virus Replication through an Akt-Independent Mechanism. J. Virol. 83: 11665-11672 [Abstract] [Full Text]  


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