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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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Cartoon of the initiation of an uncontrolled persistent virus infection or a controlled acute virus infection in immunocompetent adults.Dendritic cells (DC) present viral peptide/MHC complexes to activate T cells. There is an initial expansion phase following infections that lead to either clearance of the virus or virus persistence. For virus clearance, following the acute infection positive immune regulators (IL-2, IFN-γ, TNF, etc.) are generated that expand the effector virus-specific T cell pool, resulting in elimination of virally infected cells, termination of the infection, and resultant development of immune memory. By contrast, with viruses that persist there is a decreased expansion, and in some cases deletion, of virus-specific T cells. Remaining T cells become exhausted or hyporesponsive and are defective in the release of positive immune regulators and hence are unable to terminate the virus infection. The cause is the virus' induction of negative regulators of the immune response, i.e., IL-10 and PD-L1, and the cure is the blockade of such negative regulators with appropriate antibodies (see [12]–[14]).
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ppat-1000523-g001: Cartoon of the initiation of an uncontrolled persistent virus infection or a controlled acute virus infection in immunocompetent adults.Dendritic cells (DC) present viral peptide/MHC complexes to activate T cells. There is an initial expansion phase following infections that lead to either clearance of the virus or virus persistence. For virus clearance, following the acute infection positive immune regulators (IL-2, IFN-γ, TNF, etc.) are generated that expand the effector virus-specific T cell pool, resulting in elimination of virally infected cells, termination of the infection, and resultant development of immune memory. By contrast, with viruses that persist there is a decreased expansion, and in some cases deletion, of virus-specific T cells. Remaining T cells become exhausted or hyporesponsive and are defective in the release of positive immune regulators and hence are unable to terminate the virus infection. The cause is the virus' induction of negative regulators of the immune response, i.e., IL-10 and PD-L1, and the cure is the blockade of such negative regulators with appropriate antibodies (see [12]–[14]).

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)

Cartoon of the initiation of an uncontrolled persistent virus infection or a controlled acute virus infection in immunocompetent adults.Dendritic cells (DC) present viral peptide/MHC complexes to activate T cells. There is an initial expansion phase following infections that lead to either clearance of the virus or virus persistence. For virus clearance, following the acute infection positive immune regulators (IL-2, IFN-γ, TNF, etc.) are generated that expand the effector virus-specific T cell pool, resulting in elimination of virally infected cells, termination of the infection, and resultant development of immune memory. By contrast, with viruses that persist there is a decreased expansion, and in some cases deletion, of virus-specific T cells. Remaining T cells become exhausted or hyporesponsive and are defective in the release of positive immune regulators and hence are unable to terminate the virus infection. The cause is the virus' induction of negative regulators of the immune response, i.e., IL-10 and PD-L1, and the cure is the blockade of such negative regulators with appropriate antibodies (see [12]–[14]).
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2713431&req=5

ppat-1000523-g001: Cartoon of the initiation of an uncontrolled persistent virus infection or a controlled acute virus infection in immunocompetent adults.Dendritic cells (DC) present viral peptide/MHC complexes to activate T cells. There is an initial expansion phase following infections that lead to either clearance of the virus or virus persistence. For virus clearance, following the acute infection positive immune regulators (IL-2, IFN-γ, TNF, etc.) are generated that expand the effector virus-specific T cell pool, resulting in elimination of virally infected cells, termination of the infection, and resultant development of immune memory. By contrast, with viruses that persist there is a decreased expansion, and in some cases deletion, of virus-specific T cells. Remaining T cells become exhausted or hyporesponsive and are defective in the release of positive immune regulators and hence are unable to terminate the virus infection. The cause is the virus' induction of negative regulators of the immune response, i.e., IL-10 and PD-L1, and the cure is the blockade of such negative regulators with appropriate antibodies (see [12]–[14]).
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