Stochastic effects are important in intrahost HIV evolution even when viral loads are high
Blood plasma viral loads and the time to progress to AIDS differ widely among untreated HIV-infected humans. Although people with certain HLA (HLA-I) alleles are more likely to control HIV infections without therapy, the majority of such untreated individuals exhibit high viral loads and progress to...
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| Format: | Article |
| Language: | en_US |
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National Academy of Sciences (U.S.)
2013
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| Online Access: | http://hdl.handle.net/1721.1/78837 https://orcid.org/0000-0003-1268-9602 |
| _version_ | 1826204352146046976 |
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| author | Read, Elizabeth L. Tovo-Dwyer, Allison A. Chakraborty, Arup K |
| author2 | Massachusetts Institute of Technology. Institute for Medical Engineering & Science |
| author_facet | Massachusetts Institute of Technology. Institute for Medical Engineering & Science Read, Elizabeth L. Tovo-Dwyer, Allison A. Chakraborty, Arup K |
| author_sort | Read, Elizabeth L. |
| collection | MIT |
| description | Blood plasma viral loads and the time to progress to AIDS differ widely among untreated HIV-infected humans. Although people with certain HLA (HLA-I) alleles are more likely to control HIV infections without therapy, the majority of such untreated individuals exhibit high viral loads and progress to AIDS. Stochastic effects are considered unimportant for evolutionary dynamics in HIV-infected people when viral load is high or when selective forces strongly drive mutation. We describe a computational study of host–pathogen interaction demonstrating that stochastic effects can have a profound influence on disease dynamics, even in cases of high viral load and strong selective pressure. These stochastic effects are pronounced when the virus must traverse a fitness “barrier” in sequence space to escape the host’s cytotoxic T-lymphocyte (CTL) response, as often occurs when a fitness defect imposed by a CTL-driven mutation must be compensated for by other mutations. These “barrier-crossing” events are infrequent and stochastic, resulting in divergent disease outcomes in genetically identical individuals infected by the same viral strain. Our results reveal how genetic determinants of the CTL response control the probability with which an individual is able to control HIV infection indefinitely, and thus provide clues for vaccine design. |
| first_indexed | 2024-09-23T12:52:55Z |
| format | Article |
| id | mit-1721.1/78837 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T12:52:55Z |
| publishDate | 2013 |
| publisher | National Academy of Sciences (U.S.) |
| record_format | dspace |
| spelling | mit-1721.1/788372022-09-28T10:39:48Z Stochastic effects are important in intrahost HIV evolution even when viral loads are high Read, Elizabeth L. Tovo-Dwyer, Allison A. Chakraborty, Arup K Massachusetts Institute of Technology. Institute for Medical Engineering & Science Massachusetts Institute of Technology. Department of Biological Engineering Massachusetts Institute of Technology. Department of Chemical Engineering Massachusetts Institute of Technology. Department of Chemistry Massachusetts Institute of Technology. Department of Physics Ragon Institute of MGH, MIT and Harvard Chakraborty, Arup K. Read, Elizabeth L. Tovo-Dwyer, Allison A. Blood plasma viral loads and the time to progress to AIDS differ widely among untreated HIV-infected humans. Although people with certain HLA (HLA-I) alleles are more likely to control HIV infections without therapy, the majority of such untreated individuals exhibit high viral loads and progress to AIDS. Stochastic effects are considered unimportant for evolutionary dynamics in HIV-infected people when viral load is high or when selective forces strongly drive mutation. We describe a computational study of host–pathogen interaction demonstrating that stochastic effects can have a profound influence on disease dynamics, even in cases of high viral load and strong selective pressure. These stochastic effects are pronounced when the virus must traverse a fitness “barrier” in sequence space to escape the host’s cytotoxic T-lymphocyte (CTL) response, as often occurs when a fitness defect imposed by a CTL-driven mutation must be compensated for by other mutations. These “barrier-crossing” events are infrequent and stochastic, resulting in divergent disease outcomes in genetically identical individuals infected by the same viral strain. Our results reveal how genetic determinants of the CTL response control the probability with which an individual is able to control HIV infection indefinitely, and thus provide clues for vaccine design. Jane Coffins Childs Foundation Massachusetts Institute of Technology. Ragon Institute of MGH, MIT and Harvard National Institutes of Health (U.S.) (Director’s Pioneer Award) 2013-05-07T15:58:38Z 2013-05-07T15:58:38Z 2012-10 2012-04 Article http://purl.org/eprint/type/JournalArticle 0027-8424 1091-6490 http://hdl.handle.net/1721.1/78837 Read, E. L., A. A. Tovo-Dwyer, and A. K. Chakraborty. “Stochastic Effects Are Important in Intrahost HIV Evolution Even When Viral Loads Are High.” Proceedings of the National Academy of Sciences 109.48 (2012): 19727–19732. https://orcid.org/0000-0003-1268-9602 en_US http://dx.doi.org/10.1073/pnas.1206940109 Proceedings of the National Academy of Sciences of the United States of America Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf National Academy of Sciences (U.S.) PNAS |
| spellingShingle | Read, Elizabeth L. Tovo-Dwyer, Allison A. Chakraborty, Arup K Stochastic effects are important in intrahost HIV evolution even when viral loads are high |
| title | Stochastic effects are important in intrahost HIV evolution even when viral loads are high |
| title_full | Stochastic effects are important in intrahost HIV evolution even when viral loads are high |
| title_fullStr | Stochastic effects are important in intrahost HIV evolution even when viral loads are high |
| title_full_unstemmed | Stochastic effects are important in intrahost HIV evolution even when viral loads are high |
| title_short | Stochastic effects are important in intrahost HIV evolution even when viral loads are high |
| title_sort | stochastic effects are important in intrahost hiv evolution even when viral loads are high |
| url | http://hdl.handle.net/1721.1/78837 https://orcid.org/0000-0003-1268-9602 |
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