{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T13:35:29Z","timestamp":1785245729474,"version":"3.55.0"},"reference-count":54,"publisher":"The Royal Society","issue":"1740","license":[{"start":{"date-parts":[[2012,4,4]],"date-time":"2012-04-04T00:00:00Z","timestamp":1333497600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/royalsociety.org\/journals\/ethics-policies\/data-sharing-mining\/"}],"content-domain":{"domain":["royalsocietypublishing.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2012,8,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>With its high mutation rate, HIV is capable of escape from recognition, suppression and\/or killing by CD8+ cytotoxic T lymphocytes (CTLs). The rate at which escape variants replace each other can give insights into the selective pressure imposed by single CTL clones. We investigate the effects of specific characteristics of the HIV life cycle on the dynamics of immune escape. First, it has been found that cells in HIV-infected patients can carry multiple copies of proviruses. To investigate how this process affects the emergence of immune escape, we develop a mathematical model of HIV dynamics with multiple infections of cells. Increasing the frequency of multiple-infected cells delays the appearance of immune escape variants, slows down the rate at which they replace the wild-type variant and can even prevent escape variants from taking over the quasi-species. Second, we study the effect of the intracellular eclipse phase on the rate of escape and show that escape rates are expected to be slower than previously anticipated. In summary, slow escape rates do not necessarily imply inefficient CTL-mediated killing of HIV-infected cells, but are at least partly a result of the specific characteristics of the viral life cycle.<\/jats:p>","DOI":"10.1098\/rspb.2012.0328","type":"journal-article","created":{"date-parts":[[2012,4,4]],"date-time":"2012-04-04T07:08:25Z","timestamp":1333523305000},"page":"3003-3010","update-policy":"https:\/\/doi.org\/10.1098\/crossmark-policy","source":"Crossref","is-referenced-by-count":10,"title":["Impaired immune evasion in HIV through intracellular delays and multiple infection of cells"],"prefix":"10.1098","volume":"279","author":[{"given":"Christian L.","family":"Althaus","sequence":"first","affiliation":[{"name":"Theoretical Biology and Bioinformatics, Utrecht University, 3584 CH Utrecht, The Netherlands 1"},{"name":"Institute of Social and Preventive Medicine (ISPM), University of Bern, 3012 Bern, Switzerland 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rob J.","family":"De Boer","sequence":"additional","affiliation":[{"name":"Theoretical Biology and Bioinformatics, Utrecht University, 3584 CH Utrecht, The Netherlands 1"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"175","published-online":{"date-parts":[[2012,4,4]]},"reference":[{"key":"2025123107541836300_RSPB20120328C1","doi-asserted-by":"publisher","first-page":"453","DOI":"10.1038\/354453a0","article-title":"Human immunodeficiency virus genetic variation that can escape cytotoxic T cell recognition","volume":"354","author":"Phillips,","year":"1991","journal-title":"Nature"},{"key":"2025123107541836300_RSPB20120328C2","doi-asserted-by":"publisher","first-page":"630","DOI":"10.1038\/nri1417","article-title":"HIV and SIV CTL escape: implications for vaccine design","volume":"4","author":"Goulder,","year":"2004","journal-title":"Nat. Rev. Immunol."},{"key":"2025123107541836300_RSPB20120328C3","doi-asserted-by":"publisher","first-page":"641","DOI":"10.1038\/nature07746","article-title":"Adaptation of HIV-1 to human leukocyte antigen class I","volume":"458","author":"Kawashima,","year":"2009","journal-title":"Nature"},{"key":"2025123107541836300_RSPB20120328C4","doi-asserted-by":"publisher","first-page":"1253","DOI":"10.1084\/jem.20090365","article-title":"The first T cell response to transmitted\/founder virus contributes to the control of acute viremia in HIV-1 infection","volume":"206","author":"Goonetilleke,","year":"2009","journal-title":"J. Exp. Med."},{"key":"2025123107541836300_RSPB20120328C5","doi-asserted-by":"publisher","first-page":"e12303","DOI":"10.1371\/journal.pone.0012303","article-title":"Transmission of single HIV-1 genomes and dynamics of early immune escape revealed by ultra-deep sequencing","volume":"5","author":"Fischer,","year":"2010","journal-title":"PLoS ONE"},{"key":"2025123107541836300_RSPB20120328C6","doi-asserted-by":"publisher","first-page":"10 518","DOI":"10.1128\/JVI.00655-11","article-title":"Fitness costs and diversity of the cytotoxic T lymphocyte (CTL) response determine the rate of CTL escape during acute and chronic phases of HIV infection","volume":"85","author":"Ganusov,","year":"2011","journal-title":"J. Virol."},{"key":"2025123107541836300_RSPB20120328C7","doi-asserted-by":"publisher","first-page":"e90","DOI":"10.1371\/journal.pbio.0040090","article-title":"Inefficient cytotoxic T lymphocyte-mediated killing of HIV-1-infected cells in vivo","volume":"4","author":"Asquith,","year":"2006","journal-title":"PLoS Biol."},{"key":"2025123107541836300_RSPB20120328C8","doi-asserted-by":"publisher","first-page":"e24","DOI":"10.1371\/journal.pcbi.0020024","article-title":"Estimating costs and benefits of CTL escape mutations in SIV\/HIV infection","volume":"2","author":"Ganusov,","year":"2006","journal-title":"PLoS Comput. Biol"},{"key":"2025123107541836300_RSPB20120328C9","doi-asserted-by":"publisher","first-page":"e1000103","DOI":"10.1371\/journal.pcbi.1000103","article-title":"Dynamics of immune escape during HIV\/SIV infection","volume":"4","author":"Althaus,","year":"2008","journal-title":"PLoS Comput. Biol"},{"key":"2025123107541836300_RSPB20120328C10","doi-asserted-by":"publisher","first-page":"e1000981","DOI":"10.1371\/journal.pcbi.1000981","article-title":"Quantifying the impact of human immunodeficiency virus-1 escape from cytotoxic T-lymphocytes","volume":"6","author":"Kadolsky,","year":"2010","journal-title":"PLoS Comput. Biol."},{"key":"2025123107541836300_RSPB20120328C11","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1038\/418144a","article-title":"Multiply infected spleen cells in HIV patients","volume":"418","author":"Jung,","year":"2002","journal-title":"Nature"},{"key":"2025123107541836300_RSPB20120328C12","doi-asserted-by":"publisher","first-page":"180","DOI":"10.1002\/bies.10386","article-title":"Recombination in HIV and the evolution of drug resistance: for better or for worse?","volume":"26","author":"Bretscher,","year":"2004","journal-title":"Bioessays"},{"key":"2025123107541836300_RSPB20120328C13","doi-asserted-by":"publisher","first-page":"489","DOI":"10.1098\/rsif.2005.0064","article-title":"HIV recombination: what is the impact on antiretroviral therapy?","volume":"2","author":"Fraser,","year":"2005","journal-title":"J. R. Soc. Interface"},{"key":"2025123107541836300_RSPB20120328C14","doi-asserted-by":"publisher","first-page":"13 572","DOI":"10.1128\/JVI.79.21.13572-13578.2005","article-title":"Stochastic interplay between mutation and recombination during the acquisition of drug resistance mutations in human immunodeficiency virus type 1","volume":"79","author":"Althaus,","year":"2005","journal-title":"J. Virol."},{"key":"2025123107541836300_RSPB20120328C15","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1016\/j.epidem.2008.11.001","article-title":"Recombination and drug resistance in HIV: population dynamics and stochasticity","volume":"1","author":"Kouyos,","year":"2009","journal-title":"Epidemics"},{"key":"2025123107541836300_RSPB20120328C16","doi-asserted-by":"publisher","first-page":"8942","DOI":"10.1128\/JVI.78.16.8942-8945.2004","article-title":"Multiplicity of human immunodeficiency virus infections in lymphoid tissue","volume":"78","author":"Dixit,","year":"2004","journal-title":"J. Virol."},{"key":"2025123107541836300_RSPB20120328C17","doi-asserted-by":"publisher","first-page":"8198","DOI":"10.1073\/pnas.0407498102","article-title":"HIV dynamics with multiple infections of target cells","volume":"102","author":"Dixit,","year":"2005","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2025123107541836300_RSPB20120328C18","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1098\/rsif.2010.0266","article-title":"Effect of different modes of viral spread on the dynamics of multiply infected cells in human immunodeficiency virus infection","volume":"8","author":"Wodarz,","year":"2011","journal-title":"J. R. Soc. Interface"},{"key":"2025123107541836300_RSPB20120328C19","doi-asserted-by":"publisher","first-page":"11 199","DOI":"10.1073\/pnas.1107729108","article-title":"Majority of CD+4 T cells from peripheral blood of HIV-1-infected individuals contain only one HIV DNA molecule","volume":"108","author":"Josefsson,","year":"2011","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2025123107541836300_RSPB20120328C20","doi-asserted-by":"publisher","first-page":"e1000660","DOI":"10.1371\/journal.pcbi.1000660","article-title":"Recombination rate and selection strength in HIV intra-patient evolution","volume":"6","author":"Neher,","year":"2010","journal-title":"PLoS Comput. Biol."},{"key":"2025123107541836300_RSPB20120328C21","doi-asserted-by":"publisher","first-page":"5661","DOI":"10.1073\/pnas.1102036108","article-title":"Estimate of effective recombination rate and average selection coefficient for HIV in chronic infection","volume":"108","author":"Batorsky,","year":"2011","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2025123107541836300_RSPB20120328C22","doi-asserted-by":"publisher","first-page":"2326","DOI":"10.1111\/j.1558-5646.2009.00727.x","article-title":"Multiple HIV-1 infection of cells and the evolutionary dynamics of cytotoxic T lymphocyte escape mutants","volume":"63","author":"Wodarz,","year":"2009","journal-title":"Evolution"},{"key":"2025123107541836300_RSPB20120328C23","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1177\/135965350400900216","article-title":"Estimates of intracellular delay and average drug efficacy from viral load data of HIV-infected individuals under antiretroviral therapy","volume":"9","author":"Dixit,","year":"2004","journal-title":"Antivir. Ther."},{"key":"2025123107541836300_RSPB20120328C24","doi-asserted-by":"publisher","first-page":"7659","DOI":"10.1128\/JVI.01799-08","article-title":"Reassessing the human immunodeficiency virus type 1 life cycle through age-structured modeling: life span of infected cells, viral generation time, and basic reproductive number, R0","volume":"83","author":"Althaus,","year":"2009","journal-title":"J. Virol."},{"key":"2025123107541836300_RSPB20120328C25","doi-asserted-by":"crossref","DOI":"10.1093\/oso\/9780198504184.001.0001","volume-title":"Virus dynamics: mathematical principles of immunology and virology","author":"Nowak,","year":"2000"},{"key":"2025123107541836300_RSPB20120328C26","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1038\/nri700","article-title":"Modelling viral and immune system dynamics","volume":"2","author":"Perelson,","year":"2002","journal-title":"Nat. Rev. Immunol."},{"key":"2025123107541836300_RSPB20120328C27","doi-asserted-by":"publisher","first-page":"985","DOI":"10.1126\/science.274.5289.985","article-title":"Quantitative image analysis of HIV-1 infection in lymphoid tissue","volume":"274","author":"Haase,","year":"1996","journal-title":"Science"},{"key":"2025123107541836300_RSPB20120328C28","doi-asserted-by":"publisher","first-page":"507","DOI":"10.1016\/j.tim.2006.10.001","article-title":"Stochastic or deterministic: what is the effective population size of HIV-1?","volume":"14","author":"Kouyos,","year":"2006","journal-title":"Trends Microbiol."},{"key":"2025123107541836300_RSPB20120328C29","doi-asserted-by":"publisher","first-page":"1093","DOI":"10.1038\/nature03501","article-title":"Massive infection and loss of memory CD4+ T cells in multiple tissues during acute SIV infection","volume":"434","author":"Mattapallil,","year":"2005","journal-title":"Nature"},{"key":"2025123107541836300_RSPB20120328C30","doi-asserted-by":"publisher","first-page":"348","DOI":"10.1038\/msb.2010.4","article-title":"Intracellular transactivation of HIV can account for the decelerating decay of virus load during drug therapy","volume":"6","author":"Althaus,","year":"2010","journal-title":"Mol. Syst. Biol."},{"key":"2025123107541836300_RSPB20120328C31","doi-asserted-by":"publisher","first-page":"e1000906","DOI":"10.1371\/journal.pcbi.1000906","article-title":"Current estimates for HIV-1 production imply rapid viral clearance in lymphoid tissues","volume":"6","author":"De Boer,","year":"2010","journal-title":"PLoS Comput. Biol."},{"key":"2025123107541836300_RSPB20120328C32","doi-asserted-by":"publisher","first-page":"1782","DOI":"10.1016\/S0140-6736(99)02035-8","article-title":"Rapid production and clearance of HIV-1 and hepatitis C virus assessed by large volume plasma apheresis","volume":"354","author":"Ramratnam,","year":"1999","journal-title":"Lancet"},{"key":"2025123107541836300_RSPB20120328C33","doi-asserted-by":"crossref","first-page":"5087","DOI":"10.1128\/jvi.69.8.5087-5094.1995","article-title":"Lower in vivo mutation rate of human immunodeficiency virus type 1 than that predicted from the fidelity of purified reverse transcriptase","volume":"69","author":"Mansky,","year":"1995","journal-title":"J. Virol."},{"key":"2025123107541836300_RSPB20120328C34","doi-asserted-by":"publisher","first-page":"2838","DOI":"10.1128\/JVI.01914-06","article-title":"Understanding the failure of CD8+ T-cell vaccination against simian\/human immunodeficiency virus","volume":"81","author":"De Boer,","year":"2007","journal-title":"J. Virol."},{"key":"2025123107541836300_RSPB20120328C35","volume-title":"Principles of animal ecology","author":"Allee,","year":"1949"},{"key":"2025123107541836300_RSPB20120328C36","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1016\/S0169-5347(99)01683-3","article-title":"Inverse density dependence and the Allee effect","volume":"14","author":"Courchamp,","year":"1999","journal-title":"Trends Ecol. Evol."},{"key":"2025123107541836300_RSPB20120328C37","doi-asserted-by":"publisher","first-page":"2644","DOI":"10.1002\/1521-4141(200209)32:9%3C2644::AID-IMMU2644%3E3.0.CO;2-R","article-title":"Impact of antigen expression kinetics on the effectiveness of HIV-specific cytotoxic T lymphocytes","volume":"32","author":"van Baalen,","year":"2002","journal-title":"Eur. J. Immunol."},{"key":"2025123107541836300_RSPB20120328C38","doi-asserted-by":"crossref","first-page":"2746","DOI":"10.4049\/jimmunol.178.5.2746","article-title":"Gag-specific CD8+ T lymphocytes recognize infected cells before AIDS\u2013virus integration and viral protein expression","volume":"178","author":"Sacha,","year":"2007","journal-title":"J. Immunol"},{"key":"2025123107541836300_RSPB20120328C39","doi-asserted-by":"publisher","first-page":"11 703","DOI":"10.1128\/JVI.00926-07","article-title":"Pol-specific CD8+ T cells recognize simian immunodeficiency virus-infected cells prior to Nef-mediated major histocompatibility complex class I downregulation","volume":"81","author":"Sacha,","year":"2007","journal-title":"J. Virol."},{"key":"2025123107541836300_RSPB20120328C40","doi-asserted-by":"publisher","first-page":"10 907","DOI":"10.1128\/JVI.01357-10","article-title":"Simian immunodeficiency virus-specific CD8+ T cells recognize Vpr- and Rev-derived epitopes early after infection","volume":"84","author":"Sacha,","year":"2010","journal-title":"J. Virol."},{"key":"2025123107541836300_RSPB20120328C41","doi-asserted-by":"publisher","first-page":"2349","DOI":"10.1128\/JVI.00821-08","article-title":"Predicting the impact of blocking human immunodeficiency virus type 1 Nef in vivo","volume":"83","author":"Wick,","year":"2009","journal-title":"J. Virol."},{"key":"2025123107541836300_RSPB20120328C42","doi-asserted-by":"publisher","first-page":"e1000747","DOI":"10.1371\/journal.ppat.1000747","article-title":"CD8+ lymphocytes control viral replication in SIVmac239-infected Rhesus macaques without decreasing the lifespan of productively infected cells","volume":"6","author":"Klatt,","year":"2010","journal-title":"PLoS Pathog"},{"key":"2025123107541836300_RSPB20120328C43","doi-asserted-by":"publisher","first-page":"e1000748","DOI":"10.1371\/journal.ppat.1000748","article-title":"In vivo CD8+ T-cell suppression of SIV viremia is not mediated by CTL clearance of productively infected cells","volume":"6","author":"Wong,","year":"2010","journal-title":"PLoS Pathog."},{"key":"2025123107541836300_RSPB20120328C44","doi-asserted-by":"publisher","first-page":"e16468","DOI":"10.1371\/journal.pone.0016468","article-title":"Implications of CTL-mediated killing of HIV-infected cells during the non-productive stage of infection","volume":"6","author":"Althaus,","year":"2011","journal-title":"PLoS ONE"},{"key":"2025123107541836300_RSPB20120328C45","doi-asserted-by":"publisher","first-page":"11 982","DOI":"10.1128\/JVI.00946-07","article-title":"Estimating the effectiveness of simian immunodeficiency virus-specific CD8+ T cells from the dynamics of viral immune escape","volume":"81","author":"Mandl,","year":"2007","journal-title":"J. Virol."},{"key":"2025123107541836300_RSPB20120328C46","doi-asserted-by":"publisher","first-page":"e1000 728","DOI":"10.1371\/journal.ppat.1000728","article-title":"CD8+ T cell control of HIV-A known unknown","volume":"6","author":"Davenport,","year":"2010","journal-title":"PLoS Pathog."},{"key":"2025123107541836300_RSPB20120328C47","doi-asserted-by":"publisher","first-page":"5093","DOI":"10.4049\/jimmunol.1002204","article-title":"Does cytolysis by CD8+ T cells drive immune escape in HIV infection?","volume":"185","author":"Balamurali,","year":"2010","journal-title":"J. Immunol."},{"key":"2025123107541836300_RSPB20120328C48","doi-asserted-by":"publisher","first-page":"e1002200","DOI":"10.1371\/journal.pcbi.1002200","article-title":"Why don't CD8+ T cells reduce the lifespan of SIV-infected cells in vivo?","volume":"7","author":"Elemans,","year":"2011","journal-title":"PLoS Comput. Biol."},{"key":"2025123107541836300_RSPB20120328C49","doi-asserted-by":"publisher","first-page":"514","DOI":"10.1016\/j.it.2007.08.009","article-title":"Do most lymphocytes in humans really reside in the gut?","volume":"28","author":"Ganusov,","year":"2007","journal-title":"Trends Immunol."},{"key":"2025123107541836300_RSPB20120328C50","doi-asserted-by":"crossref","first-page":"5642","DOI":"10.1128\/jvi.66.9.5642-5645.1992","article-title":"Nonhomogeneous distribution of human immunodeficiency virus type 1 proviruses in the spleen","volume":"66","author":"Delassus,","year":"1992","journal-title":"J. Virol."},{"key":"2025123107541836300_RSPB20120328C51","doi-asserted-by":"publisher","first-page":"6975","DOI":"10.1073\/pnas.131056998","article-title":"Genetic drift and within-host metapopulation dynamics of HIV-1 infection","volume":"98","author":"Frost,","year":"2001","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2025123107541836300_RSPB20120328C52","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1016\/j.jtbi.2004.10.004","article-title":"Spatial models of virus-immune dynamics","volume":"233","author":"Funk,","year":"2005","journal-title":"J Theor. Biol."},{"key":"2025123107541836300_RSPB20120328C53","doi-asserted-by":"publisher","first-page":"712","DOI":"10.1016\/0042-6822(92)90038-Q","article-title":"Cell-to-cell spread of HIV-1 occurs within minutes and may not involve the participation of virus particles","volume":"186","author":"Sato,","year":"1992","journal-title":"Virology"},{"key":"2025123107541836300_RSPB20120328C54","doi-asserted-by":"publisher","first-page":"565","DOI":"10.1016\/S1074-7613(00)80483-5","article-title":"Evidence that a single peptide-MHC complex on a target cell can elicit a cytolytic T cell response","volume":"4","author":"Sykulev,","year":"1996","journal-title":"Immunity"}],"container-title":["Proceedings of the Royal Society B: Biological Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/royalsocietypublishing.org\/doi\/pdf\/10.1098\/rspb.2012.0328","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/royalsocietypublishing.org\/doi\/full-xml\/10.1098\/rspb.2012.0328","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/royalsocietypublishing.org\/rspb\/article-pdf\/279\/1740\/3003\/572963\/rspb.2012.0328.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/royalsocietypublishing.org\/rspb\/article-pdf\/279\/1740\/3003\/572963\/rspb.2012.0328.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,31]],"date-time":"2025-12-31T12:54:25Z","timestamp":1767185665000},"score":1,"resource":{"primary":{"URL":"https:\/\/royalsocietypublishing.org\/rspb\/article\/279\/1740\/3003\/74216\/Impaired-immune-evasion-in-HIV-through"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2012,4,4]]},"references-count":54,"journal-issue":{"issue":"1740","published-print":{"date-parts":[[2012,8,7]]}},"URL":"https:\/\/doi.org\/10.1098\/rspb.2012.0328","relation":{},"ISSN":["0962-8452","1471-2954"],"issn-type":[{"value":"0962-8452","type":"print"},{"value":"1471-2954","type":"electronic"}],"subject":[],"published":{"date-parts":[[2012,4,4]]},"assertion":[{"value":"2012-02-13","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2012-03-14","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2012-04-04","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}