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Overview on HTLV-1 p12, p8, p13: accomplices in persistent and viral pathogenesis

Department of and Laboratory Medicine, University of Medical Center, Kansas KS, USA

The human T-lymphotropic virus (HTLV-1) is etiologically linked to T cell leukemia/lymphoma and tropical paraparesis/HTLV-1-associated myelopathy. While the of Tax and Rex in viral replication and pathogenesis has extensively studied, recent suggests that additional proteins are essential for the virus cycle in vivo . In this we will summarize possible mechanisms evoked in the literature to how p12, p8, p30, and p13 facilitate viral infection of the host. We explore several stratagems by HTLV-1 accessory genes to immune surveillance, to establish and to deregulate cell cycle and to participate in virus-mediated cellular

Introduction

Expression of viral and replication is under the control of long terminal repeat transactivator Tax and viral RNA export Rex (Kashanchi and Brady, 2005 ). The of human T-lymphotropic virus (HTLV-1) structural protein(s) and their processing has been reviewed (Le Blanc et al. 2001 ; et al. 2011 ). Unlike animal the HTLV-1 proviral genome a unique pX region, which, alternative splicing and different initiation sites, generates viral regulatory proteins et al. 1992 ; Koralnik et al. 1993 ). complexity is remarkable and highlights the level of adaptation the virus in making the most out of its relatively genome. All regulatory proteins are in HTLV-1 cell lines and in infected with HTLV-1 et al. 2000 ; Satou et al. 2006 ; et al. 2009 ). Expression of these is absolutely essential for virus in an in vivo non-human primate for HTLV-1 (Valeri et al. 2010 ).

reading frame-I (ORF-I) the p12 protein, a small hydrophobic which can be further processed p8 (Koralnik et al. 1993 ). p12 and p8 have cellular localizations and distinct (Van Prooyen et al. 2010a ). studies indicate that of the functions once attributed to p12 belong to p8. ORF-II produces the p30 and p13 Although p13 encodes the carboxyl 87 amino acids of p30, cellular localizations and functions are different (Koralnik et al. 1993 ; et al. 2008 ; Silic-Benussi et al. 2010a ). Rex and corresponding to ORF-III and ORF-IV, are by the same doubly spliced RNA and Brady, 2005 ). HBZ is encoded a complementary minus-stranded RNA transcript the 3#x02032;-LTR (Gaudray et al. 2002 ; et al. 2006 ). In addition, the pX region produces two other proteins, and Rof (p12 Rex Orf I). This review focus on the role of HTLV-1 genes in virus infection, escape, and transformation.

Role of Regulatory Genes in Virus and Viral Spreading In Vivo

In to Tax and Rex, HTLV-1 regulatory p12, p8, p30, and p13 are not absolutely for virus replication and for the immortalization of primary T cells in vitro et al. 1997 ; Robek et al. 1998 ; et al. 2000 ). However, several have found that T cell lines immortalized HTLV-1 molecular clones p12 or p30 grow less efficiently their wild-type counterpart and are more dependent upon the of interleukin-2 (IL-2) in the media et al. 2000 ; Nicot et al. 2001 ; et al. 2009a ). Investigations using a model to study HTLV-1 in vivo suggested that p30, and p13 may all be required for viral (Bartoe et al. 2000 ; Silverman et al. ; Hiraragi et al. 2006 ). However, the discovery of a new viral gene, encoded from an overlapping minus-stranded RNA transcript from the challenged conclusions made in studies. Mutations aimed at out p12, p30, and p13 in HTLV-1 clones all affected the HBZ coding a gene necessary for virus (Matsuoka and Jeang, 2007 ; and Matsuoka, 2011 ). Recently, the of HTLV-1 regulatory genes was using new HTLV-1 molecular carrying a single viral knock-out, whereby HBZ expression was not These studies, which performed both in rabbits and in primates, clearly demonstrated only non-human primates an appropriate in vivo model for infection and replication (Valeri et al. ).

HBZ, p12, and p30 were to be essential for HTLV-1 infection and in non-human primates but p12 and p30 were in rabbits (Valeri et al. 2010 ). it appears that the requirement of p12 and p30 for in vivo is related to their to sustain HTLV-1 replication in cells (DCs) in in vitro and in infection of macaques (Valeri et al. ). These results also earlier studies showing HTLV-1 infection of DCs is essential for viral spread (Jones et al. ). These observations are very in understanding the development of adult T leukemia/lymphoma (ATLL), because must spread rapidly to its cells to establish a latent and avoid clearance by the immune

Human T-lymphotropic virus cell free virions are infectious and require cell-to-cell In this regard it is interesting to out studies that have a role for p12 in facilitating cell-to-cell spread by inducing lymphocyte antigen-1 (LFA-1) clustering on T These effects relied calcium-dependent signaling and increased factor of activated T cells transcription (Kim et al. 2006 ). p12 may play an essential role in the early stages of HTLV-1

Transcriptional Regulation of Viral by Regulatory Genes

Once the virus establishes infection it is for the virus to repress viral expression in order to reduce antigens and avoid being by the immune system. Tax and Rex are potent regulators of viral expression and Tax is the main target of cytotoxic T (CTLs; Koenig et al. 1993 ). of this, the HTLV-1 virus different ways to interfere Tax function and to reduce Tax expression. p13, and p8 all negatively regulate expression (Figure 1 ; Nicot et al. ; Andresen et al. 2011 ). Tax activates the of viral genes through the of cAMP response element-binding (CREB) and cellular coactivators protein (CBP), p300 and factor (PCAF) to the Tax-response (TRE) within the U3 region of the LTR and Brady, 2005 ). Some have demonstrated that p30 has the to attenuate the formation of active complexes on the TRE and can interact with via the KIX domain (Zhang et al. 2001 ). Tax recruits CBP/p300 via the same Tax and p30 are proposed to compete with other for CBP/p300 binding. these observations were in an over-expression experimental system and are subject to discrepancy (Nicot et al. ). In another study, whereby p30 was from an HTLV-1 molecular p30 could not decrease virus (Valeri et al. 2010 ). This is when the expression level of Tax and p30 are into account, as there is more Tax than p30 mRNA and in HTLV-1 transformed cells in than in transiently transfected which may not accurately reflect the levels of these proteins in . The relative level of these in ATLL cells in still and may also vary in distinct sub-populations. A recent study the expression level of p30 was about of tax/rex RNA in ATLL samples in vitro culturing for 2 h (Rende et al. ). However, this ratio not reflect the actual ratio in

FIGURE 1

FIGURE 1. Schematic representation of p12, p8, p30 and p13 in HTLV-1

In addition to viral gene genome-wide analysis revealed p30 modulates the transcription of numerous genes. Sixty-five genes found to be down-regulated greater 2.5-fold in the presence of p30. genes were found to be with cell signaling, cell cycle, and metabolism et al. 2009b ). In contrast to repressed only 15 cellular genes up-regulated and mostly corresponded to involved in transcription/translation and RNA processing et al. 2009b ).

A recent study that p13 is also able to with Tax transactivation. Using GST and co-immunoprecipitation assays, p13 was shown to with Tax, and its presence can Tax#x02019;s interaction with Interestingly, the fact that an amount of p300 can partially the repression by p13 on the HTLV-1 LTR reporter indicates a competition mechanism. In p13 and CBP/p300 have been to compete for Tax interaction. Notably, when p13 was expressed naturally an HTLV-1 molecular clone, it can repress viral replication. The between p13 and p30 mediation of Tax transactivation be caused by two factors. Firstly, a study showed that in transfection with an HTLV-1 clone, there was more p13 than p30 expression. Secondly, the of p13 can be greatly increased by Tax. In to p30 and p13, studies show a p12-processed p8 protein can also viral transcription through of T cell receptor (TCR) Previous studies demonstrate activation of the TCR increases viral The TCR complex consists of a variable TCR#x003B1;#x003B2; heterodimer and a non-variable transduction CD3 complex including CD3#x003B4;, CD3#x003B5;, and a TCR#x003B6; TCR signaling occurs through a of events. It is not clear how the TCR pathway viral transcription, but some suggests that lymphocyte-specific tyrosine kinase (Lck) a significant role in transduction. have demonstrated that p8 TCR signal transduction and reduces expression. When the non-canonical reticulum (ER) retention/retrieval (1#x02013;9 aa) within the amino is removed from p12, the was transported to the Golgi apparatus, another cleavage between acids 29 and 30 produced p8 and stimulated its at the cell surface. When the TCR is and forms the immunologic synapse p8 is quickly recruited to the IS. In the IS, p8 binds to the of activated T cells (LAT) and inhibits its activity, as evidenced by the phosphorylation of phospholipase C-gamma1 and Vav. A similar inhibition was when p8 was expressed from an molecular clone.

Post-Transcriptional Regulation of Viral by Regulatory Genes

In addition to prior studies show p30 can negatively regulate viral after transcription. We found p30 binds to a response element the tax/rex RNA and retains the viral RNA in the This further reduces Tax and silences virus expression et al. 2004. 2005 ). When p30 efficiently represses viral in both transient transfection and HTLV-1-infected cells, such as MT2 and (Nicot et al. 2004 ). Interestingly, studies demonstrated that of p30 from an HTLV-1 molecular reduced replication; and HBZ suppressed replication by targeting p30 mRNA and Ratner, 2011 ).

We recently that p30 interacts with (PA28#x003B3;) and recruits it to the tax/rex The binding of PA28#x003B3; to tax/rex RNA is In 293FT cells knocked-down for expression, viral production transfected HTLV-1 molecular significantly increased. In an HTLV-1 ATLL cell line, the of PA28#x003B3; increased tax/rex RNA and Tax These studies support the that endogenous p30 expressed physiological conditions from the can regulate tax/rex expression.

of HTLV-1 Small Regulatory in Host Immune Escape and

There is abundant evidence HTLV-1-specific CTLs are efficient HTLV-1-infected cells and play a role in determining the proviral (Bangham, 2000 ; Bangham and 2005 ; Akimoto et al. 2007 ; et al. 2009 ). So far, there is that most of the viral can be targeted by CTLs. However, it is accepted that the dominant of CTLs is the Tax protein. In addition, killer (NK) cells can kill HTLV-1-infected cells. this, HTLV-1 is still to establish persistent infection in its Studies show that the employs different strategies to silent. First, it represses gene expression, while in the host through proliferation of cells (Saggioro et al. 1991 ; et al. 2000 ; Rahman et al. 2012 ). the virus has also evolved to interfere with the immune of the host.

p8 Stimulates Formation of Tunnels for Infection of Neighboring

Although there is evidence cell-free HTLV-1 virus can DCs, it is generally accepted HTLV-1 is mainly transmitted cell-to-cell contacts, such as synapses and cellular conduits et al. 2005 ). Studies show p8 increases virus transmission cells through cellular Studies showed that p8 cell adhesion by inducing clustering without changing expression or affinity (Van et al. 2010b ). Immunofluorescence demonstrated p8 co-localized with the clustered It was further proved that p8 from the HTLV-1 molecular had the same effects (Van et al. 2010b ). The HTLV-1 virus through the conduits, as evidenced by the of mature viral particles at the site between two conduits or a conduit and the surface of the target T Collectively, p8 provides the virus a new way to infect cells hiding immune defenses (Van et al. 2010b ).

Down-Modulation of MHC-1 by p12

T lymphocytes target HTLV-1-infected through the TCR, which the viral peptide presented by the histocompatibility complex class I The MHC-1 consists of a heavy (Hc) containing the peptide site and #x003B2;2-microglobulin, which are in the lumen of the ER. Viral peptides, by the proteasome, are transported into the ER, the three components assemble in complexes and are transported to the cell The abnormality of the assembly and trafficking of helps the infected cells to recognition by the CTL, contributing to persistence. Studies show p12 interferes with the assembly and from the cell surface p12 specifically binds to newly less glycosylated MHC-1-Hc it forms a heterodimer with (Johnson et al. 2001 ; Johnson and 2002 ). Three different MHC-1-Hc-A2, B7, and Cw4 complexes were and all of them interacted with Upon binding, the MHC-1-Hc and p12 is rerouted to the cytosol and degraded by the Cellular immunofluorescence demonstrated p12 also interfered with the of MHC-1 and, consequently, the of MHC-1 on the cell surface In addition, in the presence of p12, a of endogenous MHC-1 was also (Johnson et al. 2001 ). Moreover, the molecules were decreased primary CD4 + T cells were by the HTLV-1 virus (Johnson et al. ).

Reduction of ICAM-1 and ICAM-2 by p12

As above, the HTLV-1 virus cell surface MHC-1 to CTLs. At the same time, the of MHC-1 may expose the infected to NK cells. It is also known Tax increases IL-2 expression et al. 1988 ; Ruben et al. 1988 ), promotes NK cell proliferation and LFA-1-mediated adhesion of NK cells to adhesion molecules (ICAMs) on cells. Taken together, suggests that NK cells can adhere to and kill HTLV-1-infected (Stewart et al. 1996 ). Surprisingly, show there was little between NK cell cytotoxicity of the cells and the HTLV-1-infected cells. pretreatment of cells with just marginally increased NK cytotoxicity to HTLV-1-infected cells. studies demonstrated that infection specifically decreased the of ICAM-1 and ICAM-2, but not ICAM-3 on T cells (Banerjee et al. 2007 ). it was demonstrated that expression of p12 is sufficient to down-modulate them et al. 2007 ). In addition, lack of cytotoxicity receptor (NCR) and ligand expression from cells might also NK cell activity. So far, it is not whether p12 or p8 mediate the down-modulation of and ICAM-2, and the mechanism for doing so remains to be seen.

Inhibition of Signaling by p30 in Macrophages

Although the target of HTLV-1 is CD4 + cells, other kinds of cells can be infected both in vivo and in . such as monocytes, macrophages, and DCs et al. 2009 ). These cells are for innate immunity and play a role in antigen presentation. are some reports stating infection by HTLV-1 interferes the differentiation and function of DCs. Our show that p30 interferes Toll-like receptor-4 (TLR-4) in human macrophages (Datta et al. ; Bai et al. 2010 ). TLR-4 is the major (LPS) receptor and elicits an immune response against bacteria. We found that p30 to and inhibits PU.1 DNA binding and p30 inhibits endogenous PU.1-mediated from a PU.1 reporter in macrophages (Datta et al. 2006 ). In p30 reduces endogenous PU.1 The inhibition of PU.1 by p30 was further by a decrease in TLR4 expression et al. 2006 ). Notably, when p30 was from an HTLV-1 molecular it still down-regulated TLR-4 Consistent with this, in the of p30, the release of pro-inflammatory monocyte chemotactic protein-1(MCP-1), necrosis factor-alpha (TNF-#x003B1;), and decreased after stimulation LPS (Datta et al. 2006 ). Although and adaptive immune responses been thought to be non-overlapping, evidence clearly indicates the interplay between components of the system occurs frequently and the basis of effective immunity. The of inhibition of PU.1 by p30 on the host response remains to be studied.

studies highlight another of macrophage and DC infection. They are not #x0201C;victims#x0201D; of the HTLV-1 virus, but may help virus transmission, and persistence (Jones et al. 2008 ). The of these observations remains to be Interestingly, an HTLV-1 molecular with p12 or p30 ablation cannot human primary DCs, that they play an role in DC infection (Valeri et al. ).


How HTLV-1 Regulatory Genes T Cell Proliferation, Affect DNA and Promote Cellular Transformation

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Activation of Stat5b by p12

Interleukin-2 is an cytokine that drives T proliferation. There are three IL-2 receptors (IL-2R): chain (IL-2R#x003B1;), #x003B2; (IL-2R#x003B2;), and #x003B3; chain also known as the common receptor #x003B3; chain c )]. Ligand-specific IL-R#x003B1; (CD25) is on activated lymphocytes and binds with low affinity. The IL-2R#x003B2;/IL-2R#x003B3; binds IL-2 with affinity. When all three are expressed on activated T cells, is bound with high The intermediate and high affinity forms are responsible for IL-2 transduction (Waldmann et al. 1998 ; and Leonard, 2000 ). Binding of leads to the heterodimerization of the cytoplasmic of IL-2R#x003B2; and #x003B3; c . followed by the of Janus kinase 1 (Jak1) and Then, Jak1 and Jak3 signal transducers and activators of (STAT) proteins through IL-2R#x003B2; is essential for STAT docking and activation (Waldmann et al. ; Imada and Leonard, 2000 ). In cells, there exists activation of the Jak/STAT pathway et al. 1995. 1998 ; Xu et al. 1995 ; et al. 1997 ). Although Tax can activate the pathway through inducing IL-2R#x003B1;, and STAT5 expression, the that there is little or no Tax in the majority of ATLL patient indicates that another exists. p12 has the ability to activate the pathway. p12 significantly increased the activity and DNA binding of STAT5b et al. 2001 ). The activation required the IL-2R#x003B2;, #x003B3; c . and Jak3. expression of p12 in peripheral blood cells (PBMCs) also in more STAT5 phosphorylation and DNA Consistent with the activation of the pathway by p12, t p12 decreases the requirement for T cell proliferation and cell proliferation by limiting the of IL-2 (Nicot et al. 2001 ). In p12 also increases the colony potential of HTLV-1 with and IL-2. It is notable that p12 was expressed naturally in the HTLV-1 clone, it still decreased the dependency on IL-2 (Nicot et al. ).

p12 Deregulates Ca 2+ and NFAT

Except for the pathway, p12 also has the ability to another important T cell factor, the NFAT. There are members in the NFAT family. them, NFAT1 to NFAT4 are by intracellular Ca 2+ signaling and, in T cells, NFAT2 is the predominantly factor. Purified NFAT is phosphorylated and is dephosphorylated by the phosphatase All kinds of stimuli that NFAT will first in the release of Ca 2+ from the ER. The released Ca 2+ in the activates the Ca 2+ sensor calmodulin, by the activation of the calmodulin-dependent phosphatase, (Medyouf and Ghysdael, 2008 ; and Rao, 2009 ). Calcineurin multiple phosphoserines from the domain of NFAT and activates The activated NFAT translocates the nucleus and cooperates with factors, including activator (AP-1), to activate transcription. ability to activate NFAT is to its ability to increase cytoplasmic Ca 2+ et al. 2002 ; Ding et al. 2002 ; Kim et al. ). In support of this conclusion, can be blocked by BAPTA-AM [glycine, N,N N -2-(acetyloxy) methoxy-2-oxoethyl]-[bis(acetyloxy)methyl ester], a of intracellular calcium. How p12 increases calcium is not clear. However, 2-APB, an inositol 1,4,5-trisphosphate receptor, and SKF 96365, a chemical of release-activated calcium (CRAC) in the plasma membrane, can partially the activation implies that ER calcium releasing and extracellular-calcium contribute to the cytoplasmic calcium In addition, cyclosporin A and a dominant NFAT2 mutant also the activation by p12. It is also that p12 has a calcineurin binding PSLP(I/L)T, which is highly to the PXIXIT calcineurin binding of NFAT. p12 binds to calcineurin and with NFAT for calcineurin (Albrecht et al. 2002 ; Ding et al. ; Kim et al. 2003 ). Because both STAT5 and NFAT can bind to the promoter and increase transcription, the of p12 should enhance IL-2 As expected, p12 expression in Jurkat T and PBMCs enhances IL-2 The enhanced IL-2 production by p12 was which suggests that the pathway might be even important to p12 in enhancing IL-2 In addition, the quantities of IL-2 from p12-expressing PBMCs sufficient to promote PBMC Interestingly, we found that increased HTLV-1 virus We further demonstrated that of Jak/STAT signaling decreased transmission. Transmission was associated promotion of cell membrane but not with virus production, adherence, gags polarization, or synapse formation. This remains to be clarified. Except for all the of IL-2, it also stimulates CTL and evokes NK cell cytotoxicity HTLV-1-infected cells, helping to them.

p30 Alters Cell Cycle and DNA to Promote Transformation

Using analysis, the effect of p30 on gene was studied by two different groups et al. 2007 ; Taylor et al. 2009b ). on the changes in gene expression, p30 many aspects of cell such as apoptosis, cell T cell activation and signal and transcription/translation/RNA processing factors. p30 down-regulates more genes it up-regulates. We also studied the of p30 on RNA export and found that p30 or decreased a large portion of in the cytoplasm. The biological significance of changes remains to be tested. It is of that all these assays based on over-expression systems. on the array data, p30 was tested on AP-1, and NFAT reporters and without co-stimulators of T cells, phorbol 12-myristate 13-acetate ionomycin, anti-CD3, and anti-CD28. p30 all three reporters in Jurkat T (Datta et al. 2007 ). Collectively, data suggested that like p12, has the potential to T cell proliferation. However, the of p30 in regulating the cell cycle of T is not yet determined, and so far three studies had different results. In one study, it was that p30 results in a delay in the G2 of the cell cycle (Datta et al. ). In addition, the p30 transduced Jurkat T proliferated slowly compared to the cells. The delay was associated the G2-M transition checkpoint, phosphorylation of checkpoint kinase-1 at serine 345, phosphorylation of at serine 216, reduced of Polo-like kinase-1 (PLK1) and the 210 phosphorylated form of PLK1 and of Cdc2 at threonine 198 and 216 (Datta et al. ). However, in another study it was that p30 inhibits G1-S and retains cells in G1 in both and Jurkat T cells (Baydoun et al. ). p30 prevents S phase entry by multiple checkpoints, as evidenced by phosphorylation of retinoblastoma protein decreased expression of E2F, cell nuclear antigen and Cyclin E, and increased expression of p21 waf et al. 2010 ). In addition, we demonstrated p30 interacts with both and Cyclin E and reduces active E complex formation (Baydoun et al. ). Because Tax promotes cell progression, especially at the G1-S transition (Franchini et al. 2003 ), p30 has a new way to regulate Tax. Further are needed to understand the function of p30 on cycle and the relationship(s) between of the cell cycle, viral and leukemogenesis.

In addition to deregulation of the cycle, p30 also interferes DNA repair to promote cancer. In a study, it was found that p30 homologous recombination (HR) (Baydoun et al. 2011 ). When was a DNA double strand break caused by drugs or irradiation, p30 from the nucleoli to the nucleoplasm. p30 was associated with phosphorylation of p30 at 232 by the mitogen-activated protein kinase signaling pathway, since was blocked by a threonine to alanine at 232 of p30 and the MAPK inhibitor, PD98059 et al. 2011 ). Several pieces of indicated that amino 221#x02013;254 of p30#x02019;s c-terminus are not in HR. Notably, p30 was demonstrated to interact both nibrin (NBS1) and but not MRE11, and p30 was able to reduce the of functional Mre11#x02013;Rad50#x02013;NBS1 (MRN) onto DSBs (Baydoun et al. ). Moreover, p30 also disrupted the MRN formation on naturally occurring during S-phase. Corresponding to a in HR repair was an increase in error-prone end-joining (NHEJ) repair. these data suggest p30 increases the instability of the genome and an important role in T cell and leukemogenesis (Baydoun et al. 2011 ). Our is consistent with the facts p30 protects cells from a topoisomerase I inhibitor, which apoptosis in cells in the S phase of the cycle, and irradiation. A recent also showed that p30 to ataxia telangiectasia mutated and modulates its phosphorylation to prevent (Anupam et al. 2011 ). In addition to genomic instability, p30 also transformation through enhancing the and transforming activity of Myc. p30 with both Myc and TIP60 and Myc to recruit more TIP60 to the Myc complex (Awasthi et al. 2005 ).

The Role of p13 in Pro-Apoptosis and Inhibition of Cell Proliferation

p13 localizes to nuclear speckles and mitochondria on the cellular context and expression (D#x02019;Agostino et al. 2000 ). The amino 21#x02013;30 of p13, the minimal targeting sequence, are responsible for targeting. Studies show p13 might form an amphipathic helix across the inner and trigger an inward K + and Ca + current causes depolarization, activation of the transport chain and augmentation of oxygen species (ROS) (Silic-Benussi et al. 2009. 2010c ; et al. 2010 ). Further studies that even at lower levels or through expression in the of the viral genome, p13 can increase ROS and induce apoptosis (D#x02019;Agostino et al. ; Hiraragi et al. 2005 ). There is that p13 can significantly reduce the and growth rate of tumors from c-myc and ha-ras-co-transfected rat fibroblasts (Silic-Benussi et al. 2004 ). It is not if p13 has the same function when it is at lower levels or in its natural Interestingly, later studies that p13 also increased ROS in normal primary T cells and T cells, which was not associated apoptosis (Silic-Benussi et al. 2010b ). The was specific because mutant p13 did not the same effect. Altogether it is that p13 might help the infected cells #x0201C;normal#x0201D; selectively killing the transformed cells. More studies are before we can understand how p13 functions in the of infection.

Conclusion

Human virus type-1 persistence on establishment of latency. p12, p8, and p13 play critical functions to the virus to establish latency, immune surveillance and promote (Figure 2 ). After infection and the establishment of an effective immune to HTLV-1, Tax and Rex can be expressed at high producing as much virus as to infect and transform as many as possible. At the same time p13, p30, and HBZ interfere Tax-mediated transcription and reduce the level of viral expression, p30 tax/rex RNA and reduces Tax and Rex directly. the host acquires immunity HTLV-1, especially Tax, the cells with less Tax cell regulation and/or of p30, p13, and HBZ can survive. to maintain the infection and transform the a low level of Tax expression is still The presence of p12 helps the infected to avoid being recognized by CTL or NK p30 can deregulate innate immune and p8 increases the efficiency of virus

FIGURE 2. The contributions of p12, p8, p30 and p13 for the of persistent infection and cell

In addition, p12 and p30 can compensate for the low expression of Tax by T cell proliferation and increasing DNA thereby transforming cells. The also evolves ways to some negative regulations, as HBZ decreasing p30 expression and Rex inhibiting p30 and tax/rex export. These prevent the absolute latency of the In conclusion, the concerted expression of p8, p30, and p13 help the virus to and maintain an incomplete latency in the virus expresses low levels of proteins. In turn, these the infection and transformation at the same that they evade surveillance.

Conflict of Interest

References

Akimoto, M. Kozako, T. T. Matsushita, K. Ozaki, A. Hamada, H. et al. Anti-HTLV-1 tax antibody and tax-specific T lymphocyte are associated with a in HTLV-1 proviral load in carriers. J. Med. Virol. 79,

Zhang, W. Nisbet, J. W. Albrecht, B. W. Kashanchi, F. Bartoe, J. T. et al. (2001). T-lymphotropic virus type 1 regulates gene transcription by CREB binding protein/p300. J. 75, 9885#x02013;9895.

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