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Modifications of keratinocyte functions by human papillomaviruses

2005; Wiley; Volume: 14; Issue: 10 Linguagem: Inglês

10.1111/j.1600-0625.2005.0355j.x

1600-0625

Herbert Pfister,

Poxvirus research and outbreaks

Human papilloma viruses (HPVs) infect keratinocytes of skin and mucosa. They affect the homeostasis of these stratified epithelia to support their replication cycle, which closely parallels the keratinocyte differentiation program. In basal cells, early viral genes are only weakly expressed to guarantee maintenance of the viral DNA. As infected cells leave the basal layer, they remain active in the cell cycle in contrast to uninfected keratinocytes due to the action of the viral oncoproteins E6 and E7, which interfere with cell-cycle control factors. This ensures cellular DNA polymerase activity and thus allows vegetative viral DNA replication. The activation of apoptotic pathways in infected keratinocytes is blocked by E6, interfering with pro-apoptotic factors. Deregulation of cell growth and inhibition of apoptosis primarily serve the HPV life cycle, but in cases of undue expression of viral oncogenes, different subsets of HPV types play a key role in the development of anogenital cancer, head and neck cancer, and squamous cell skin carcinomas. Under experimental conditions, human keratinocytes are efficiently immortalized by E6 and E7 of high-risk mucosal HPV associated with anogenital cancers. The viral oncoproteins furthermore alter cytokine expression patterns of keratinocytes and interfere with cytokine signaling to fight both innate and adaptive immune responses of the host. The viral E2 protein seems to counterbalance the effects of oncoproteins on keratinocyte function. It can induce apoptosis and cooperates with cellular transcription factors involved in keratinocyte differentiation. The E4 protein is abundantly expressed in the late phases of the viral life cycle. It induces cell-cycle arrest in G2, may be to further counteract the effects of E7. It also associates with keratin networks, sometimes inducing their collapse and, may be facilitating viral egress from keratinocyte squames. Longworth M S, Laimins L A. Pathogenesis of human papilloma viruses in differentiating epithelia. Microbiol Mol Biol Rev 2004: 68: 362–372. This article is a good review of the various effects of viral proteins on keratinocyte function in the productive viral life cycle and in carcinogenesis, strictly focussing on mucosal, mainly high-risk HPV types, where most of the genetic and biochemical work has been performed. Longworth M S, Wilson R, Laimins L A. HPV31 E7 facilitates replication by activating E2F2 transcription through its interaction with HDACs. EMBO J 2005: 24: 1821–1830. E7 was shown to activate E2F2 transcription in suprabasal keratinocytes by binding histone deacetylase (HDAC) and inhibiting HDAC binding to the E2F2 promoter. E2F2 expression facilitates HPV replication, but siRNA-mediated reduction did not affect cell proliferation, highlighting the ‘real interest’ of the virus. Garner-Hamrick P A, Fostel J M, Chien W M, et al. Global effects of human papilloma virus type 18, E6/E7 in an organotypic keratinocyte culture system. J Virol 2004: 78: 9041–9050. This article highlights the complexity of effects of E6/E7 expression, which significantly altered the expression of 1381 genes associated with DNA and RNA metabolism, cell cycle, and cell differentiation. Caldeira S, Zehbe I, Accardi R, et al. The E6 and E7 proteins of the cutaneous human papilloma virus type 38 display transforming properties. J Virol 2003: 77: 2195–2206. The cutaneous HPV38 E7 is able to inactivate the tumor suppressor pRb and to relieve G1/S transition control similar to mucosal high-risk HPV but in contrast to the cutaneous HPV10 and HPV20. HPV38 E6 and E7 induce long-lasting proliferation of primary human keratinocytes. Smola-Hess S, Pahne J, Mauch C, Zigrino P, Smola H, Pfister H J. Expression of membrane type 1 matrix metalloproteinase in papillomavirus-positive cells: role of the human papilloma virus (HPV) 16 and HPV18 E7 gene products. J Gen Virol 2005: 86: 1291–1296. Expression of E7 from the mucosal and cutaneous high-risk types HPV16 and HPV8 induced MT1-MMP expression in primary human keratinocytes and HaCaT cells, which led to the activation of MMP-2. This may be relevant to the viral life cycle by promoting keratinocyte proliferation and may contribute to keratinocyte invasion during tumor progression. Akgül B, Garcia-Escudero R, Ghali L, et al. The E7 protein of cutaneous human papilloma virus type 8 causes invasion of human keratinocytes into the dermis in organotypic cultures of skin. Cancer Res 2005: 65: 2216–2223. Expression of the cutaneous HPV8 E7 gene caused hyperproliferation of keratinocytes as well as migration and invasion through the underlying dermis in organotypis raft culture. The basement membrane was disrupted accompanied by the overexpression of matrix metalloproteinases MMP-1, MMP-8, and MT1-MMP. Pett M R, Alazawi W O, Roberts I, et al. Acquisition of high-level chromosomal instability is associated with integration of human papilloma virus type 16 in cervical keratinocytes. Cancer Res 2004: 64: 1359–1368. Acquisition of an unstable host genome is a key step in cervical carcinogenesis. This article shows that the integration of HPV16 and increased E7 protein levels precede chromosomal instability. Intermediate E7 levels are associated with numerical chromosomal abnormalities and maximal levels also lead to structural aberrations. Smola-Hess S, Pfister H. Immune evasion in genital papillomavirus infection and cervical cancer. role of cytokines and chemokines. In: Campo M S, ed. Papillomavirus Research from Natural History to Vaccines and Beyond. Wymondham: Caister Academic Press, 2006: 321–339. This review addresses the regulation of cytokine expression in HPV-infected keratinocytes and interference of HPV with cytokine or chemokine signals. It discusses the consequences for immune evasion of HPV. Boccardo E, Noya F, Broker T R, Chow L T, Villa L L. HPV-18 confers resistance to TNF-alpha in organotypic cultures of human keratinocytes. Virology 2004: 328: 233–243. TNF-alpha is one of the main mediators of inflammation in the skin and mucosa and a potent inhibitor of normal human keratinocyte proliferation. It is shown that HPV18 E7 alone is able to confer partial resistance to TNF-alpha arrest of S-phase entry and that whole genomic HPV18 DNA confers almost complete resistance to this cytokine. Yuan H, Fu F, Zhuo J, et al. Human papilloma virus type 16, E6 and E7 oncoproteins upregulate c-IAP2 gene expression and confer resistance to apoptosis. Oncogene 2005 April 25: [Epub ahead of print]. HPV16 E6/E7 upregulates the transcription of the cellular inhibitor of apoptosis protein 2 (c-IAP2) dependent on NF-κB activity. Using c-IAP2 RNA interference, it could be shown that c-IAP2 is necessary for HPV16 E6/E7-induced resistance to apoptosis. Oldak M, Smola H, Aumailley M, Rivero F, Pfister H, Smola-Hess S. The human papilloma virus type 8, E2 protein suppresses beta4-integrin expression in primary human keratinocytes. J Virol 2004 78: 10738–10746. HPV8 E2 expression strongly downregulates β4-integrin expression, partially by binding to an E2 recognition site within the cellular promoter. Also β1-integrin is partially reduced. HPV8 E2-expressing keratinocytes detach from underlying structures. In vivo, high E2 expression may push infected basal keratinocytes into the transit-amplifying compartment to trigger virus replication. Hadaschik D, Hinterkeuser K, Oldak M, Pfister H J, Smola-Hess S. The Papillomavirus E2 protein binds to and synergizes with C/EBP factors involved in keratinocyte differentiation. J Virol 2003: 77: 5253–5265. The E2 proteins of HPV8, HPV16, and HPV18 interact with the cellular transcription factors C/EBP-alpha and -beta and synergistically transactivate the involucrin gene. This may contribute to enhancing keratinocyte differentiation to finalize the viral life cycle. Knight G L, Grainger J R, Gallimore P H, Roberts S. Cooperation between different forms of the human papilloma virus type 1, E4 protein to block cell cycle progression and cellular DNA synthesis. J Virol 2004 78: 13920–13933. A truncated 16K E4 protein of the plantar wart virus HPV1 mediates a G2 arrest in the cell cycle, whereas coexpression of full-length and truncated E4 protein inhibited cellular DNA replication on top of the arrest in G2. It is suggested that E4 has to keep keratinocytes in a metabolically active state without competing host DNA synthesis to maximize viral DNA amplification. Thanks to the help of Chanel, Galderma International, Laboratoires Bailleul, Laboratoires Pierre Fabre, Laboratoires Serobiologiques, La Roche Posay Laboratoire Pharmaceutique, Leo Pharma, and L.V.M.H.