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Anatomy of viral persistence.

Oldstone MB - PLoS Pathog. (2009)

View Article: PubMed Central - PubMed

Affiliation: Viral Immunobiology Laboratory, Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA, USA. mbaobo@scripps.edu

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We do know that acutely infected cells express viral peptides, which, when attached to host major histocompatibility complex (MHC) molecules on their surfaces, signal the immune system to kill such cells... Similarly, to persist in infected cells, viruses can disrupt the processing or migration of viral peptides or viral peptide/MHC complexes to the cells' surface, thereby removing the recognition signals for activated killer T cells... A similar scenario occurs with the in utero or neonatal murine retroviral infections... Further, circulating and glomerular-deposited v-Ab complexes are found in humans with persistent viral infections... In the LCMV persistent infection induced in adults, IL-10 is produced primarily by virus-infected cDCs and perhaps by B cells... In vivo, neither CD4 nor CD8 T cells produce significant amounts of IL-10... Interestingly, although IL-10 plays a major role in T cell exhaustion of adult mice persistently infected with LCMV, as yet no similar role for IL-10 has been found in the persistent infection of adults infected in utero or neonatally (D... Blockade of PD-L1 by specific antibody restores T cell function, which then allows these effector T cells to control the virus infection... The exploration and understanding of negative immune regulators, including IL-10 and PD-1, are still at an early stage; nevertheless, the implications are important and profound... First, exhausted or hyporesponsive T cells found in persistent infections can be resurrected to functional capacity... Clearance of a persistent LCMV infection requires virus-specific CD4 T cell help to assist virus-specific CD8 T cells –... Some examples are the development of pharmacologic small molecules as effective antagonists of negative immune regulators, the use of transient negative regulator blockers as an adjuvant approach to enhance both prophylactic and therapeutic vaccination, and the determination of how long during the course of persistent virus infection exhausted T cells can be rescued to become antiviral effector T cells... As always, the goal is to understand basic principles in viral pathogenesis and to extend results in the murine model to resolve persistent infections of humans.

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The scenario of virus induction of negative regulators leading to T cell hyporesponsiveness sprung from experimental analysis of LCMV infection in its natural murine host using inoculation of parental LCMV Armstrong strain 53B or its variant, LCMV Cl 13.The 10.7-kb genome of these viruses differs by only six nucleotides that code for three amino acids. One amino acid located in the viral spike protein GP-1 at aa 260 (Leu Cl 13/Phe ARM 53b) is responsible for high affinity binding (2.5 logs higher affinity for Cl 13 over ARM 53b) for the LCMV receptor alpha-dystroglycan, which is located in the immune system, preferentially on DCs (see [32],[33]). A second important mutation is in the viral polymerase at aa 1079 (Leu Cl 13/Gln ARM 53b) and is associated with enhanced transcription and replication of LCMV Cl 13. Recent studies have also implicated infection of the fibroblastic reticular cells in lymphoid organs as contributing to the persistent infection (see [34]). Figure 2 shows this using a whole body section of a mouse. The tissue section was placed on a membrane and stained with a riboprobe to LCMV at 30 days after initiation of LCMV infection with either LCMV Cl 13 or LCMV ARM 53b. The presence of viral nucleic acids in mice receiving Cl 13 correlates directly with high titers of virus carried in the sera (PFU/ml) at 30 days post-infection and the lack of a CTL response observed 7 days after initiation of infection. By comparison, mice receiving LCMV ARM 53b at 30 days post-infection fail to display viral nucleic acid sequences or virus in their sera, as virus has been successfully purged. Further, mice infected with LCMV ARM 53b generate a robust CTL response 7 days following virus infection.
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ppat-1000523-g002: The scenario of virus induction of negative regulators leading to T cell hyporesponsiveness sprung from experimental analysis of LCMV infection in its natural murine host using inoculation of parental LCMV Armstrong strain 53B or its variant, LCMV Cl 13.The 10.7-kb genome of these viruses differs by only six nucleotides that code for three amino acids. One amino acid located in the viral spike protein GP-1 at aa 260 (Leu Cl 13/Phe ARM 53b) is responsible for high affinity binding (2.5 logs higher affinity for Cl 13 over ARM 53b) for the LCMV receptor alpha-dystroglycan, which is located in the immune system, preferentially on DCs (see [32],[33]). A second important mutation is in the viral polymerase at aa 1079 (Leu Cl 13/Gln ARM 53b) and is associated with enhanced transcription and replication of LCMV Cl 13. Recent studies have also implicated infection of the fibroblastic reticular cells in lymphoid organs as contributing to the persistent infection (see [34]). Figure 2 shows this using a whole body section of a mouse. The tissue section was placed on a membrane and stained with a riboprobe to LCMV at 30 days after initiation of LCMV infection with either LCMV Cl 13 or LCMV ARM 53b. The presence of viral nucleic acids in mice receiving Cl 13 correlates directly with high titers of virus carried in the sera (PFU/ml) at 30 days post-infection and the lack of a CTL response observed 7 days after initiation of infection. By comparison, mice receiving LCMV ARM 53b at 30 days post-infection fail to display viral nucleic acid sequences or virus in their sera, as virus has been successfully purged. Further, mice infected with LCMV ARM 53b generate a robust CTL response 7 days following virus infection.

Mentions: Currently our laboratory and others are engaged in the discovery of additional negative immune regulators and their signaling pathway(s) using gene chip and forward genetics technology. These projects have a multitude of applications. Some examples are the development of pharmacologic small molecules as effective antagonists of negative immune regulators, the use of transient negative regulator blockers as an adjuvant approach to enhance both prophylactic and therapeutic vaccination, and the determination of how long during the course of persistent virus infection exhausted T cells can be rescued to become antiviral effector T cells. As always, the goal is to understand basic principles in viral pathogenesis and to extend results in the murine model to resolve persistent infections of humans.


Anatomy of viral persistence.

Oldstone MB - PLoS Pathog. (2009)

The scenario of virus induction of negative regulators leading to T cell hyporesponsiveness sprung from experimental analysis of LCMV infection in its natural murine host using inoculation of parental LCMV Armstrong strain 53B or its variant, LCMV Cl 13.The 10.7-kb genome of these viruses differs by only six nucleotides that code for three amino acids. One amino acid located in the viral spike protein GP-1 at aa 260 (Leu Cl 13/Phe ARM 53b) is responsible for high affinity binding (2.5 logs higher affinity for Cl 13 over ARM 53b) for the LCMV receptor alpha-dystroglycan, which is located in the immune system, preferentially on DCs (see [32],[33]). A second important mutation is in the viral polymerase at aa 1079 (Leu Cl 13/Gln ARM 53b) and is associated with enhanced transcription and replication of LCMV Cl 13. Recent studies have also implicated infection of the fibroblastic reticular cells in lymphoid organs as contributing to the persistent infection (see [34]). Figure 2 shows this using a whole body section of a mouse. The tissue section was placed on a membrane and stained with a riboprobe to LCMV at 30 days after initiation of LCMV infection with either LCMV Cl 13 or LCMV ARM 53b. The presence of viral nucleic acids in mice receiving Cl 13 correlates directly with high titers of virus carried in the sera (PFU/ml) at 30 days post-infection and the lack of a CTL response observed 7 days after initiation of infection. By comparison, mice receiving LCMV ARM 53b at 30 days post-infection fail to display viral nucleic acid sequences or virus in their sera, as virus has been successfully purged. Further, mice infected with LCMV ARM 53b generate a robust CTL response 7 days following virus infection.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2713431&req=5

ppat-1000523-g002: The scenario of virus induction of negative regulators leading to T cell hyporesponsiveness sprung from experimental analysis of LCMV infection in its natural murine host using inoculation of parental LCMV Armstrong strain 53B or its variant, LCMV Cl 13.The 10.7-kb genome of these viruses differs by only six nucleotides that code for three amino acids. One amino acid located in the viral spike protein GP-1 at aa 260 (Leu Cl 13/Phe ARM 53b) is responsible for high affinity binding (2.5 logs higher affinity for Cl 13 over ARM 53b) for the LCMV receptor alpha-dystroglycan, which is located in the immune system, preferentially on DCs (see [32],[33]). A second important mutation is in the viral polymerase at aa 1079 (Leu Cl 13/Gln ARM 53b) and is associated with enhanced transcription and replication of LCMV Cl 13. Recent studies have also implicated infection of the fibroblastic reticular cells in lymphoid organs as contributing to the persistent infection (see [34]). Figure 2 shows this using a whole body section of a mouse. The tissue section was placed on a membrane and stained with a riboprobe to LCMV at 30 days after initiation of LCMV infection with either LCMV Cl 13 or LCMV ARM 53b. The presence of viral nucleic acids in mice receiving Cl 13 correlates directly with high titers of virus carried in the sera (PFU/ml) at 30 days post-infection and the lack of a CTL response observed 7 days after initiation of infection. By comparison, mice receiving LCMV ARM 53b at 30 days post-infection fail to display viral nucleic acid sequences or virus in their sera, as virus has been successfully purged. Further, mice infected with LCMV ARM 53b generate a robust CTL response 7 days following virus infection.
Mentions: Currently our laboratory and others are engaged in the discovery of additional negative immune regulators and their signaling pathway(s) using gene chip and forward genetics technology. These projects have a multitude of applications. Some examples are the development of pharmacologic small molecules as effective antagonists of negative immune regulators, the use of transient negative regulator blockers as an adjuvant approach to enhance both prophylactic and therapeutic vaccination, and the determination of how long during the course of persistent virus infection exhausted T cells can be rescued to become antiviral effector T cells. As always, the goal is to understand basic principles in viral pathogenesis and to extend results in the murine model to resolve persistent infections of humans.

View Article: PubMed Central - PubMed

Affiliation: Viral Immunobiology Laboratory, Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA, USA. mbaobo@scripps.edu

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

We do know that acutely infected cells express viral peptides, which, when attached to host major histocompatibility complex (MHC) molecules on their surfaces, signal the immune system to kill such cells... Similarly, to persist in infected cells, viruses can disrupt the processing or migration of viral peptides or viral peptide/MHC complexes to the cells' surface, thereby removing the recognition signals for activated killer T cells... A similar scenario occurs with the in utero or neonatal murine retroviral infections... Further, circulating and glomerular-deposited v-Ab complexes are found in humans with persistent viral infections... In the LCMV persistent infection induced in adults, IL-10 is produced primarily by virus-infected cDCs and perhaps by B cells... In vivo, neither CD4 nor CD8 T cells produce significant amounts of IL-10... Interestingly, although IL-10 plays a major role in T cell exhaustion of adult mice persistently infected with LCMV, as yet no similar role for IL-10 has been found in the persistent infection of adults infected in utero or neonatally (D... Blockade of PD-L1 by specific antibody restores T cell function, which then allows these effector T cells to control the virus infection... The exploration and understanding of negative immune regulators, including IL-10 and PD-1, are still at an early stage; nevertheless, the implications are important and profound... First, exhausted or hyporesponsive T cells found in persistent infections can be resurrected to functional capacity... Clearance of a persistent LCMV infection requires virus-specific CD4 T cell help to assist virus-specific CD8 T cells –... Some examples are the development of pharmacologic small molecules as effective antagonists of negative immune regulators, the use of transient negative regulator blockers as an adjuvant approach to enhance both prophylactic and therapeutic vaccination, and the determination of how long during the course of persistent virus infection exhausted T cells can be rescued to become antiviral effector T cells... As always, the goal is to understand basic principles in viral pathogenesis and to extend results in the murine model to resolve persistent infections of humans.

Show MeSH
Related in: MedlinePlus