HTLV-1 HBZ: stop making sense
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《血液学杂志》
An antisense-encoded protein of HTLV-1 is dispensable for infection and transformation of T cells in vitro, yet modulates viral infectivity and persistence in vivo. Negative-strand–encoded retrovirus proteins may provide new targets for attenuating viral replication and pathogenesis.
The recent observation that human T-cell leukemia virus type-1 (HTLV-1) encodes an antisense viral gene product HTLV-1 b-ZIP protein (HBZ) has resulted in intense focus and investigation into the role and function of this novel protein in viral infection.1 Even more compelling evidence indicates that HBZ counteracts the transcriptional transactivation mediated by the HTLV-1 Tax oncoprotein by interfering with the DNA binding activity of JunB and c-Jun.2 In this issue of Blood, Arnold and colleagues generate HBZ mutant viruses to characterize the role of HBZ on HTLV-1 infection in vitro and in vivo.
Basic leucine region zipper (b-ZIP) factors have been shown to be crucial components in the transcriptional regulation of genes, involving many cellular processes including proliferation, transformation, and apoptosis.3 Previously, investigators have demonstrated that overexpression of HBZ down modulates Tax1-induced transcriptional transactivation in transient transfection studies by interfering with the cellular transcription factors comprising the AP-1 complex and suppressing transcriptional activity.1,4 Although adult T-cell leukemia (ATL) cells often contain deletions of the HTLV-1 proviral sequences, the 3' end of the provirus encompassing the Tax gene is invariably maintained in leukemic cells from patients. Since the HTLV-1 Tax oncoprotein plays a central role in immortalization of lymphocytes for growth in vitro and in the early stages of leukemogenesis in infected patients, the observation that HBZ down modulates Tax function is intriguing and implies an additional level of complexity in the regulation of HTLV-1 gene expression, which may ultimately impact viral latency and persistence. In the current issue of Blood, Arnold et al investigate the role of HBZ in the context of viral replication (see figure). Deletion of HBZ in an infectious proviral clone of HTLV-1 had no effect on the ability of the virus to replicate and immortalize lymphocytes for growth in culture. Disruption of HBZ did, however, result in significant reductions in proviral load and in an attenuated antibody response against viral proteins when infection was established in the rabbit model. Furthermore, HBZ protein function is distinct and separate from any potential siRNA effects, as was recently described for the antisense transcript encoded in the 3' end of the HIV-1 provirus.5 Mutations that disrupt the leucine zipper domain of HBZ demonstrate identical phenotypes compared with mutant viruses that are completely attenuated for HBZ, suggesting that this domain is required for protein interactions and transcriptional repression.
Detection of the HBZ RNA transcript. See the complete figure in the article beginning on page 3976.
Use of negative-strand viral gene products in the regulation of HTLV-1 infection not only establishes a new framework for investigations of virus replication but also provides a novel target for antiviral drug intervention. Still lacking is the determination of the precise role of HBZ in oncogenesis resulting from HTLV-1 infection as well as a mechanistic understanding of HBZ activities during the course of viral persistence and latency. It is interesting to speculate that HBZ may function synergistically with the HTLV-1 accessory protein p30II to govern and throttle the transcriptional transactivation mediated by the Tax oncoprotein and that these activities provide a selective advantage in the maintenance of infection in vivo. An additional question is whether HTLV-2, a virus highly related to HTLV-1 that is not associated with leukemogenesis, also encodes for HBZ. Although HTLV-1 infection can be established in rabbits, the development of animal models that recapitulate HTLV-1 pathogenesis is a critical and challenging endeavor that will allow full characterization of the functions of these viral proteins.
References
Gaudray G, Gachon F, Basbous J, Biard-Piechaczyk M, Devaux C, Mesnard JM. The complementary strand of the human T-cell leukemia virus type 1 RNA genome encodes a bZIP transcription factor that down-regulates viral transcription. J Virol. 2002;76: 12813-12822.
Basbous J, Arpin C, Gaudray G, Piechaczyk M, Devaux C, Mesnard JM. The HBZ factor of human T-cell leukemia virus type I dimerizes with transcription factors JunB and c-Jun and modulates their transcriptional activity. J Biol Chem. 2003;278: 43620-43627.
Angel P, Karin M. The role of Jun, Fos and the AP-1 complex in cell-proliferation and transformation. Biochim Biophys Acta. 1991;1072: 129-157.
Matsumoto J, Ohshima T, Isono O, Shimotohno K. HTLV-1 HBZ suppresses AP-1 activity by impairing both the DNA-binding ability and the stability of c-Jun protein. Oncogene. 2005;24: 1001-1010.
Bennasser Y, Le SY, Benkirane M, Jeang KT. Evidence that HIV-1 encodes an siRNA and a suppressor of RNA silencing. Immunity. 2005;22: 607-619.(Gerold Feuer)
The recent observation that human T-cell leukemia virus type-1 (HTLV-1) encodes an antisense viral gene product HTLV-1 b-ZIP protein (HBZ) has resulted in intense focus and investigation into the role and function of this novel protein in viral infection.1 Even more compelling evidence indicates that HBZ counteracts the transcriptional transactivation mediated by the HTLV-1 Tax oncoprotein by interfering with the DNA binding activity of JunB and c-Jun.2 In this issue of Blood, Arnold and colleagues generate HBZ mutant viruses to characterize the role of HBZ on HTLV-1 infection in vitro and in vivo.
Basic leucine region zipper (b-ZIP) factors have been shown to be crucial components in the transcriptional regulation of genes, involving many cellular processes including proliferation, transformation, and apoptosis.3 Previously, investigators have demonstrated that overexpression of HBZ down modulates Tax1-induced transcriptional transactivation in transient transfection studies by interfering with the cellular transcription factors comprising the AP-1 complex and suppressing transcriptional activity.1,4 Although adult T-cell leukemia (ATL) cells often contain deletions of the HTLV-1 proviral sequences, the 3' end of the provirus encompassing the Tax gene is invariably maintained in leukemic cells from patients. Since the HTLV-1 Tax oncoprotein plays a central role in immortalization of lymphocytes for growth in vitro and in the early stages of leukemogenesis in infected patients, the observation that HBZ down modulates Tax function is intriguing and implies an additional level of complexity in the regulation of HTLV-1 gene expression, which may ultimately impact viral latency and persistence. In the current issue of Blood, Arnold et al investigate the role of HBZ in the context of viral replication (see figure). Deletion of HBZ in an infectious proviral clone of HTLV-1 had no effect on the ability of the virus to replicate and immortalize lymphocytes for growth in culture. Disruption of HBZ did, however, result in significant reductions in proviral load and in an attenuated antibody response against viral proteins when infection was established in the rabbit model. Furthermore, HBZ protein function is distinct and separate from any potential siRNA effects, as was recently described for the antisense transcript encoded in the 3' end of the HIV-1 provirus.5 Mutations that disrupt the leucine zipper domain of HBZ demonstrate identical phenotypes compared with mutant viruses that are completely attenuated for HBZ, suggesting that this domain is required for protein interactions and transcriptional repression.
Detection of the HBZ RNA transcript. See the complete figure in the article beginning on page 3976.
Use of negative-strand viral gene products in the regulation of HTLV-1 infection not only establishes a new framework for investigations of virus replication but also provides a novel target for antiviral drug intervention. Still lacking is the determination of the precise role of HBZ in oncogenesis resulting from HTLV-1 infection as well as a mechanistic understanding of HBZ activities during the course of viral persistence and latency. It is interesting to speculate that HBZ may function synergistically with the HTLV-1 accessory protein p30II to govern and throttle the transcriptional transactivation mediated by the Tax oncoprotein and that these activities provide a selective advantage in the maintenance of infection in vivo. An additional question is whether HTLV-2, a virus highly related to HTLV-1 that is not associated with leukemogenesis, also encodes for HBZ. Although HTLV-1 infection can be established in rabbits, the development of animal models that recapitulate HTLV-1 pathogenesis is a critical and challenging endeavor that will allow full characterization of the functions of these viral proteins.
References
Gaudray G, Gachon F, Basbous J, Biard-Piechaczyk M, Devaux C, Mesnard JM. The complementary strand of the human T-cell leukemia virus type 1 RNA genome encodes a bZIP transcription factor that down-regulates viral transcription. J Virol. 2002;76: 12813-12822.
Basbous J, Arpin C, Gaudray G, Piechaczyk M, Devaux C, Mesnard JM. The HBZ factor of human T-cell leukemia virus type I dimerizes with transcription factors JunB and c-Jun and modulates their transcriptional activity. J Biol Chem. 2003;278: 43620-43627.
Angel P, Karin M. The role of Jun, Fos and the AP-1 complex in cell-proliferation and transformation. Biochim Biophys Acta. 1991;1072: 129-157.
Matsumoto J, Ohshima T, Isono O, Shimotohno K. HTLV-1 HBZ suppresses AP-1 activity by impairing both the DNA-binding ability and the stability of c-Jun protein. Oncogene. 2005;24: 1001-1010.
Bennasser Y, Le SY, Benkirane M, Jeang KT. Evidence that HIV-1 encodes an siRNA and a suppressor of RNA silencing. Immunity. 2005;22: 607-619.(Gerold Feuer)