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Dynamics of Immune Escape during HIV/SIV Infection

Several studies have shown that cytotoxic T lymphocytes (CTLs) play an important role in controlling HIV/SIV infection. Notably, the observation of escape mutants suggests a selective pressure induced by the CTL response. However, it remains difficult to assess the definite role of the cellular immu...

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Detalles Bibliográficos
Autores principales: Althaus, Christian L., De Boer, Rob J.
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2008
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2423483/
https://www.ncbi.nlm.nih.gov/pubmed/18636096
http://dx.doi.org/10.1371/journal.pcbi.1000103
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author Althaus, Christian L.
De Boer, Rob J.
author_facet Althaus, Christian L.
De Boer, Rob J.
author_sort Althaus, Christian L.
collection PubMed
description Several studies have shown that cytotoxic T lymphocytes (CTLs) play an important role in controlling HIV/SIV infection. Notably, the observation of escape mutants suggests a selective pressure induced by the CTL response. However, it remains difficult to assess the definite role of the cellular immune response. We devise a computational model of HIV/SIV infection having a broad cellular immune response targeting different viral epitopes. The CTL clones are stimulated by viral antigen and interact with the virus population through cytotoxic killing of infected cells. Consequently, the virus population reacts through the acquisition of CTL escape mutations. Our model provides realistic virus dynamics and describes several experimental observations. We postulate that inter-clonal competition and immunodominance may be critical factors determining the sequential emergence of escapes. We show that even though the total killing induced by the CTL response can be high, escape rates against a single CTL clone are often slow and difficult to estimate from infrequent sequence measurements. Finally, our simulations show that a higher degree of immunodominance leads to more frequent escape with a reduced control of viral replication but a substantially impaired replicative capacity of the virus. This result suggests two strategies for vaccine design: Vaccines inducing a broad CTL response should decrease the viral load, whereas vaccines stimulating a narrow but dominant CTL response are likely to induce escape but may dramatically reduce the replicative capacity of the virus.
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spelling pubmed-24234832008-07-18 Dynamics of Immune Escape during HIV/SIV Infection Althaus, Christian L. De Boer, Rob J. PLoS Comput Biol Research Article Several studies have shown that cytotoxic T lymphocytes (CTLs) play an important role in controlling HIV/SIV infection. Notably, the observation of escape mutants suggests a selective pressure induced by the CTL response. However, it remains difficult to assess the definite role of the cellular immune response. We devise a computational model of HIV/SIV infection having a broad cellular immune response targeting different viral epitopes. The CTL clones are stimulated by viral antigen and interact with the virus population through cytotoxic killing of infected cells. Consequently, the virus population reacts through the acquisition of CTL escape mutations. Our model provides realistic virus dynamics and describes several experimental observations. We postulate that inter-clonal competition and immunodominance may be critical factors determining the sequential emergence of escapes. We show that even though the total killing induced by the CTL response can be high, escape rates against a single CTL clone are often slow and difficult to estimate from infrequent sequence measurements. Finally, our simulations show that a higher degree of immunodominance leads to more frequent escape with a reduced control of viral replication but a substantially impaired replicative capacity of the virus. This result suggests two strategies for vaccine design: Vaccines inducing a broad CTL response should decrease the viral load, whereas vaccines stimulating a narrow but dominant CTL response are likely to induce escape but may dramatically reduce the replicative capacity of the virus. Public Library of Science 2008-07-18 /pmc/articles/PMC2423483/ /pubmed/18636096 http://dx.doi.org/10.1371/journal.pcbi.1000103 Text en Althaus, De Boer. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Althaus, Christian L.
De Boer, Rob J.
Dynamics of Immune Escape during HIV/SIV Infection
title Dynamics of Immune Escape during HIV/SIV Infection
title_full Dynamics of Immune Escape during HIV/SIV Infection
title_fullStr Dynamics of Immune Escape during HIV/SIV Infection
title_full_unstemmed Dynamics of Immune Escape during HIV/SIV Infection
title_short Dynamics of Immune Escape during HIV/SIV Infection
title_sort dynamics of immune escape during hiv/siv infection
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2423483/
https://www.ncbi.nlm.nih.gov/pubmed/18636096
http://dx.doi.org/10.1371/journal.pcbi.1000103
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