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Benefits from early treatment of HIV-1 infection
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TRENDS in Molecular Medicine Vol.7 No.1 January 2001
9
Protein shuttles, IGF-I and colorectal cancer Deregulation of the Wnt signalling pathway by constitutive activation of β-catenin/TCFmediated transcription is thought to be an initiating and possibly obligatory event in the aetiology of colorectal cancer. In normal colonic epithelium, the adenomatous polyposis coli tumour suppressor (APC), a negative regulator of the Wnt pathway, forms a complex with axin/conductin, glycogen synthase kinase 3β (GSK3β) and β-catenin, and helps target β-catenin for proteasomal degradation. In colorectal tumours this is blocked, either by loss of the APC protein or by stabilizing mutations of β-catenin. β-catenin has two functions: (1) in the cytoplasm it associates with and links E-cadherin to the actin cytoskeleton: mutations in β-catenin abolish cell-cell adhesiveness; (2) it can translocate into the nucleus, form complexes with lymphoid enhancer factor/T-cell factor (LEF/TCF) transcription factors, and activate the transcription of proto-oncogenic target genes, such as c-myc, cyclin D1 and c-jun. Subcellular redistribution and compartmental sequestration of proteins are important mechanisms in the regulation
of cellular responses. Neufeld and colleagues1 have demonstrated that endogenous, wild-type APC is able to shuttle between the nucleus and cytoplasm. Nuclear export depends on a functional interaction between two leucine-rich nuclear export sequences, NES1APC and NES2APC, and the nuclear export factor Crm1. These data suggest that nuclear APC may inhibit Wnt signalling directly by inhibiting the interaction between nuclear β-catenin and TCF. Insulin-like growth factor-I (IGF-I) signalling influences integrin-mediated cell motility and enhanced expression of its tyrosine kinase receptor, IGF-IR, is implicated in colorectal tumorigenesis. Playford et al.2 used an IGF-I-responsive colorectal cancer cell line that expresses wild-type APC, E-cadherin and β-catenin to demonstrate IGF-I-dependent phosphorylation of β-catenin. This resulted in its rapid dissociation from E-cadherin and relocation to the cytoplasm. Furthermore, the half-life of β-catenin was doubled and, in the presence of an inhibitor of GSK3β, TCF/β-catenin transcriptional activation was
increased by a factor of several thousand. Given that both APC and GSK3β have proapoptotic effects and that excess β-catenin is anti-apoptotic, these data suggest a mechanism for the anti-apoptotic effects of IGF-I signalling. Taken together, these two reports suggest that APC has a role as a global regulator of colonocyte development and provide one explanation for the increasing evidence that implicates IGF-I serum levels as an important determinant of colorectal cancer risk. References 1 Neufeld, K.L. et al. (2000) Adenematous polyposis coli protein contains two nuclear export signals and shuttles between the nucleus and cytoplasm. Proc. Natl. Acad. Sci. U. S. A. 97, 12085–12090 2 Playford, M.P. et al. (2000) Insulin-like growth factor 1 regulates the location, stability, and transcriptional activity of β-catenin. Proc. Natl. Acad. Sci. U. S. A. 97, 12103–12108
Stephen Bustin [email protected] PII: S1471-4914(00)01877-3
Benefits from early treatment of HIV-1 infection Encouraging results in the treatment of HIV-1 infection have been achieved in the last few years, after introduction of the triple therapy approach. The initial hope that the immune system might control the infection after highly active antiviral therapy (HAART) has however not been fulfilled, as the reappearance of virus has been observed after discontinuation of HAART. The early phase of the infection determines the ultimate outcome, as it is this period when immune cells that are able to control the infection start to proliferate. Unfortunately, HIV-1 replicates more efficiently in proliferating CD4 T cells, resulting in the self-elimination of the immune cells capable of dealing with the virus within the first months of infection. Rosenberg and co-workers1 recently demonstrated the importance of the early treatment of HIV-1 in a study enrolling 16 patients who were treated during acute infection. In contrast to patients treated in the chronic phase of infection, these patients displayed T-helper-cell responses similar to those observed in long-term non-
progressors. In order to investigate whether the early treatment can preserve a functional HIV-1-specific immune control, eight patients underwent supervised treatment interruptions. Three of these patients were able to control virus replication with viral load levels below 5000 RNA copies per ml of plasma after the first treatment interruption. The other five patients had to restart therapy after the first treatment interruption, because plasma virus levels exceeded the criterion for restarting treatment. Nevertheless, after a second treatment interruption four of them were able to control virus replication at levels below 5000 RNA copies per ml of plasma. Furthermore, all of the eight patients displayed increased virus-specific cytotoxic T cell levels and maintained T-helper-cell responses. These findings are confirmed by results obtained in another recent study by Hel and co-workers2, who demonstrated the benefits of early treatment in addition to therapeutic vaccination in the SIV/macaque
model. These studies demonstrated the benefits of early treatment of acute HIV-1 infection on the preservation of functional HIV-1-specific immune control and provide the basis for a randomized long-term trial investigating the impact on the outcome of the disease. In addition, these data emphasize the importance of rapid tests that would allow the identification of the acute infection as early as possible. Most importantly, it would be vital to ascertain whether a supervised structured treatment interruption could increase the functional immune response in chronic HIV-1 patients. References 1 Rosenberg, E.S. et al. (2000) Immune control of HIV-1 after early treatment of acute infection. Nature 407, 523–526 2 Hel, Z. et al. (2000) Viremia control following antiretroviral treatment and therapeutic immunization during primary SIV251 infection of macaques. Nat. Med. 6, 1140–1146
Dieter Klein [email protected]
http://tmm.trends.com 1471-4914/01/$ – see front matter © 2001 Elsevier Science Ltd. All rights reserved. PII: S1471-4914(00)01876-1
TRENDS in Molecular Medicine Vol.7 No.1 January 2001
9
Protein shuttles, IGF-I and colorectal cancer Deregulation of the Wnt signalling pathway by constitutive activation of β-catenin/TCFmediated transcription is thought to be an initiating and possibly obligatory event in the aetiology of colorectal cancer. In normal colonic epithelium, the adenomatous polyposis coli tumour suppressor (APC), a negative regulator of the Wnt pathway, forms a complex with axin/conductin, glycogen synthase kinase 3β (GSK3β) and β-catenin, and helps target β-catenin for proteasomal degradation. In colorectal tumours this is blocked, either by loss of the APC protein or by stabilizing mutations of β-catenin. β-catenin has two functions: (1) in the cytoplasm it associates with and links E-cadherin to the actin cytoskeleton: mutations in β-catenin abolish cell-cell adhesiveness; (2) it can translocate into the nucleus, form complexes with lymphoid enhancer factor/T-cell factor (LEF/TCF) transcription factors, and activate the transcription of proto-oncogenic target genes, such as c-myc, cyclin D1 and c-jun. Subcellular redistribution and compartmental sequestration of proteins are important mechanisms in the regulation
of cellular responses. Neufeld and colleagues1 have demonstrated that endogenous, wild-type APC is able to shuttle between the nucleus and cytoplasm. Nuclear export depends on a functional interaction between two leucine-rich nuclear export sequences, NES1APC and NES2APC, and the nuclear export factor Crm1. These data suggest that nuclear APC may inhibit Wnt signalling directly by inhibiting the interaction between nuclear β-catenin and TCF. Insulin-like growth factor-I (IGF-I) signalling influences integrin-mediated cell motility and enhanced expression of its tyrosine kinase receptor, IGF-IR, is implicated in colorectal tumorigenesis. Playford et al.2 used an IGF-I-responsive colorectal cancer cell line that expresses wild-type APC, E-cadherin and β-catenin to demonstrate IGF-I-dependent phosphorylation of β-catenin. This resulted in its rapid dissociation from E-cadherin and relocation to the cytoplasm. Furthermore, the half-life of β-catenin was doubled and, in the presence of an inhibitor of GSK3β, TCF/β-catenin transcriptional activation was
increased by a factor of several thousand. Given that both APC and GSK3β have proapoptotic effects and that excess β-catenin is anti-apoptotic, these data suggest a mechanism for the anti-apoptotic effects of IGF-I signalling. Taken together, these two reports suggest that APC has a role as a global regulator of colonocyte development and provide one explanation for the increasing evidence that implicates IGF-I serum levels as an important determinant of colorectal cancer risk. References 1 Neufeld, K.L. et al. (2000) Adenematous polyposis coli protein contains two nuclear export signals and shuttles between the nucleus and cytoplasm. Proc. Natl. Acad. Sci. U. S. A. 97, 12085–12090 2 Playford, M.P. et al. (2000) Insulin-like growth factor 1 regulates the location, stability, and transcriptional activity of β-catenin. Proc. Natl. Acad. Sci. U. S. A. 97, 12103–12108
Stephen Bustin [email protected] PII: S1471-4914(00)01877-3
Benefits from early treatment of HIV-1 infection Encouraging results in the treatment of HIV-1 infection have been achieved in the last few years, after introduction of the triple therapy approach. The initial hope that the immune system might control the infection after highly active antiviral therapy (HAART) has however not been fulfilled, as the reappearance of virus has been observed after discontinuation of HAART. The early phase of the infection determines the ultimate outcome, as it is this period when immune cells that are able to control the infection start to proliferate. Unfortunately, HIV-1 replicates more efficiently in proliferating CD4 T cells, resulting in the self-elimination of the immune cells capable of dealing with the virus within the first months of infection. Rosenberg and co-workers1 recently demonstrated the importance of the early treatment of HIV-1 in a study enrolling 16 patients who were treated during acute infection. In contrast to patients treated in the chronic phase of infection, these patients displayed T-helper-cell responses similar to those observed in long-term non-
progressors. In order to investigate whether the early treatment can preserve a functional HIV-1-specific immune control, eight patients underwent supervised treatment interruptions. Three of these patients were able to control virus replication with viral load levels below 5000 RNA copies per ml of plasma after the first treatment interruption. The other five patients had to restart therapy after the first treatment interruption, because plasma virus levels exceeded the criterion for restarting treatment. Nevertheless, after a second treatment interruption four of them were able to control virus replication at levels below 5000 RNA copies per ml of plasma. Furthermore, all of the eight patients displayed increased virus-specific cytotoxic T cell levels and maintained T-helper-cell responses. These findings are confirmed by results obtained in another recent study by Hel and co-workers2, who demonstrated the benefits of early treatment in addition to therapeutic vaccination in the SIV/macaque
model. These studies demonstrated the benefits of early treatment of acute HIV-1 infection on the preservation of functional HIV-1-specific immune control and provide the basis for a randomized long-term trial investigating the impact on the outcome of the disease. In addition, these data emphasize the importance of rapid tests that would allow the identification of the acute infection as early as possible. Most importantly, it would be vital to ascertain whether a supervised structured treatment interruption could increase the functional immune response in chronic HIV-1 patients. References 1 Rosenberg, E.S. et al. (2000) Immune control of HIV-1 after early treatment of acute infection. Nature 407, 523–526 2 Hel, Z. et al. (2000) Viremia control following antiretroviral treatment and therapeutic immunization during primary SIV251 infection of macaques. Nat. Med. 6, 1140–1146
Dieter Klein [email protected]
http://tmm.trends.com 1471-4914/01/$ – see front matter © 2001 Elsevier Science Ltd. All rights reserved. PII: S1471-4914(00)01876-1