{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T02:16:26Z","timestamp":1792462586317,"version":"4.5.0"},"reference-count":57,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[1999,11,1]],"date-time":"1999-11-01T00:00:00Z","timestamp":941414400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[1999,11,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The pattern and process of evolution in the nef gene of HIV-1 was analyzed within and among patients. Using a maximum likelihood method that allows for variable intensity of selection pressure among codons, strong positive selection was detected in a hemophiliac patient over 30 mo of infection. By reconstructing the process of allele substitution in this patient using parsimony, the synapomorphic amino acid changes separating each time point were found to have high probabilities of being under positive selection, with selective coefficients of at least 3.6%. Positive selection was also detected among 39 nef sequences from HIV-1 subtype B. In contrast, multiple pairwise comparisons of nonsynonymous and synonymous substitution rates provided no good evidence for positive selection and sliding window analyses failed to detect most positively selected sites. These findings demonstrate that positive selection is an important determinant of nef gene evolution and that genealogy-based methods outperform pairwise methods in the detection of adaptive evolution. Mapping the locations of positively selected sites may also be of use in identifying targets of the immune response and hence aid vaccine design.<\/jats:p>","DOI":"10.1093\/genetics\/153.3.1077","type":"journal-article","created":{"date-parts":[[2021,4,28]],"date-time":"2021-04-28T05:10:43Z","timestamp":1619586643000},"page":"1077-1089","source":"Crossref","is-referenced-by-count":95,"title":["Genealogical Evidence for Positive Selection in the nef Gene of HIV-1"],"prefix":"10.1093","volume":"153","author":[{"given":"Paolo M","family":"de A. Zanotto","sequence":"first","affiliation":[{"name":"Bioinformatics and Retrovirology Laboratory, Escola Paulista de Medicina, Universidade Federal de S\u00e3o Paulo, S\u00e3o Paulo, CEP 05508-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esper G","family":"Kallas","sequence":"additional","affiliation":[{"name":"Laboratory of Immunology DIPA\u2013Escola Paulista de Medicina, Universidade Federal de S\u00e3o Paulo, S\u00e3o Paulo, CEP 05508-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robson F","family":"de Souza","sequence":"additional","affiliation":[{"name":"Bioinformatics and Retrovirology Laboratory, Escola Paulista de Medicina, Universidade Federal de S\u00e3o Paulo, S\u00e3o Paulo, CEP 05508-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward C","family":"Holmes","sequence":"additional","affiliation":[{"name":"The Wellcome Trust Centre for the Epidemiology of Infectious Disease, Department of Zoology, University of Oxford, Oxford OX1 3PS, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[1999,11,1]]},"reference":[{"key":"2022010403442441000_R1","doi-asserted-by":"crossref","first-page":"478","DOI":"10.1038\/30996","article-title":"Help for cytotoxic-T-cell responses is mediated by CD40 signaling","volume":"393","author":"Bennett","year":"1998","journal-title":"Nature"},{"key":"2022010403442441000_R2","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1038\/376125a0","article-title":"Causes of HIV diversity","volume":"376","author":"Bonhoeffer","year":"1995","journal-title":"Nature"},{"key":"2022010403442441000_R3","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1038\/nm0297-205","article-title":"Antiviral pressure exerted by HIV-1 specific cytotoxic T lymphocytes (CTLs) during primary infection demonstrated by rapid selection of CTL escape virus","volume":"3","author":"Borrow","year":"1997","journal-title":"Nat. Med."},{"key":"2022010403442441000_R4","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1093\/oxfordjournals.molbev.a026118","article-title":"Parallel evolution of drug resistance in HIV: failure of nonsynonymous\/synonymous substitution rate ratio to detect selection","volume":"16","author":"Crandall","year":"1999","journal-title":"Mol. Biol. Evol."},{"key":"2022010403442441000_R5","doi-asserted-by":"crossref","first-page":"1259","DOI":"10.1093\/oxfordjournals.molbev.a025854","article-title":"Conservation of cytotoxic T lymphocyte (CTL) epitopes as a host strategy to constrain parasite adaptation: evidence from the nef gene of human immunodeficiency virus 1 (HIV-1)","volume":"15","author":"da Silva","year":"1998","journal-title":"Mol. Biol. Evol."},{"key":"2022010403442441000_R6","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1128\/JVI.72.1.617-623.1998","article-title":"Human immunodeficiency virus type 1 populations in blood and semen","volume":"72","author":"Delwart","year":"1998","journal-title":"J. Virol."},{"key":"2022010403442441000_R7","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1093\/oxfordjournals.molbev.a025629","article-title":"Large-scale search for genes on which positive selection may operate","volume":"13","author":"Endo","year":"1996","journal-title":"Mol. Biol. Evol."},{"key":"2022010403442441000_R8","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1038\/351290a0","article-title":"Allele-specific motifs revealed by sequencing of self-peptides eluted from MHC molecules","volume":"351","author":"Falk","year":"1991","journal-title":"Nature"},{"key":"2022010403442441000_R9","doi-asserted-by":"crossref","first-page":"4270","DOI":"10.1073\/pnas.88.10.4270","article-title":"Positive Darwinian evolution in human influenza A viruses","volume":"88","author":"Fitch","year":"1991","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2022010403442441000_R10","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1093\/genetics\/133.3.693","article-title":"Statistical tests of neutrality of mutations","volume":"133","author":"Fu","year":"1993","journal-title":"Genetics"},{"key":"2022010403442441000_R11","first-page":"725","article-title":"A codon-based method of nucleotide substitution for protein-coding DNA sequences","volume":"11","author":"Goldman","year":"1994","journal-title":"Mol. Biol. Evol."},{"key":"2022010403442441000_R12","doi-asserted-by":"crossref","first-page":"5662","DOI":"10.1128\/jvi.70.8.5662-5664.1996","article-title":"Human immunodeficiency virus in vivo: calculations based on a single zidovudine resistance mutation at codon 215 of reverse transcriptase","volume":"70","author":"Goudsmit","year":"1996","journal-title":"J. Virol."},{"key":"2022010403442441000_R13","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1038\/nm0297-212","article-title":"Late escape from an immunodominant cytotoxic T-lymphocyte response associated with progression to AIDS","volume":"3","author":"Goulder","year":"1997","journal-title":"Nat. Med."},{"key":"2022010403442441000_R14","doi-asserted-by":"crossref","first-page":"886","DOI":"10.1128\/JVI.72.1.886-887.1998","article-title":"Genetic drift of human immunodeficiency virus type 1?","volume":"72","author":"Holmes","year":"1998","journal-title":"J. Virol."},{"key":"2022010403442441000_R15","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1038\/335167a0","article-title":"Pattern of nucleotide substitution at major histocompatibility complex class I loci reveals positive selection","volume":"335","author":"Hughes","year":"1988","journal-title":"Nature"},{"key":"2022010403442441000_R16","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1097\/00002030-199808000-00005","article-title":"Characterization of the viral population during primary HIV-1 infection","volume":"12","author":"Karlsson","year":"1998","journal-title":"AIDS"},{"key":"2022010403442441000_R17","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1016\/0092-8674(91)90097-I","article-title":"Importance of the nef gene for maintenance of high virus loads and for development of AIDS","volume":"65","author":"Kestler","year":"1991","journal-title":"Cell"},{"key":"2022010403442441000_R18","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1056\/NEJM199501263320405","article-title":"Absence of intact nef sequences in a long-term survivor with nonprogressive HIV-1 infection","volume":"332","author":"Kirchhoff","year":"1995","journal-title":"N. Engl. J. Med."},{"key":"2022010403442441000_R19","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1038\/nm0495-330","article-title":"Transfer of HIV-1 specific cytotoxic T lymphocytes to an AIDS patient leads to selection for mutant HIV variants and subsequent disease progression","volume":"1","author":"Koenig","year":"1995","journal-title":"Nat. Med."},{"key":"2022010403442441000_R20","volume-title":"HIV Molecular Immunology Database 1997","author":"Korber","year":"1997"},{"key":"2022010403442441000_R21","doi-asserted-by":"crossref","DOI":"10.2172\/607510","volume-title":"Human Retrovirus and AIDS 1997","author":"Korber","year":"1997"},{"key":"2022010403442441000_R22","doi-asserted-by":"crossref","first-page":"1421","DOI":"10.1093\/genetics\/140.4.1421","article-title":"Estimating effective population size and mutation rate from sequence data using Metropolis-Hastings sampling","volume":"140","author":"Kuhner","year":"1995","journal-title":"Genetics"},{"key":"2022010403442441000_R23","volume-title":"MEGA: Molecular Evolutionary Genetics Analysis","author":"Kumar","year":"1993"},{"key":"2022010403442441000_R24","doi-asserted-by":"crossref","first-page":"1862","DOI":"10.1073\/pnas.94.5.1862","article-title":"Analysis of HIV-1 env gene sequences reveals evidence for a low effective number in the viral population","volume":"94","author":"Leigh Brown","year":"1997","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2022010403442441000_R25","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1038\/nm0397-268","article-title":"HIV-1: gambling on the evolution of drug resistance?","volume":"3","author":"Leigh Brown","year":"1997","journal-title":"Nat. Med."},{"key":"2022010403442441000_R26","volume-title":"HIV and the Pathogenesis of AIDS","author":"Levy","year":"1998","edition":"Ed. 2"},{"key":"2022010403442441000_R27","volume-title":"MacClade: Analysis of Phylogeny and Character Evolution","author":"Maddison","year":"1992"},{"key":"2022010403442441000_R28","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1016\/S0092-8674(00)81428-2","article-title":"T cell responses and viral escape","volume":"93","author":"McMichael","year":"1998","journal-title":"Cell"},{"key":"2022010403442441000_R29","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1146\/annurev.immunol.15.1.271","article-title":"Escape of human immunodeficiency virus from immune control","volume":"15","author":"McMichael","year":"1997","journal-title":"Annu. Rev. Immunol."},{"key":"2022010403442441000_R30","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1038\/385151a0","article-title":"Episodic adaptive evolution of primate lysozymes","volume":"385","author":"Messier","year":"1997","journal-title":"Nature"},{"key":"2022010403442441000_R31","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1093\/oxfordjournals.molbev.a025549","article-title":"Estimating synonymous and nonsynonymous substitution rates","volume":"13","author":"Muse","year":"1996","journal-title":"Mol. Biol. Evol."},{"key":"2022010403442441000_R32","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1084\/jem.185.2.293","article-title":"HIV-1 induces cytotoxic T lymphocytes in the cervix of infected women","volume":"185","author":"Musey","year":"1997","journal-title":"J. Exp. Med."},{"key":"2022010403442441000_R33","doi-asserted-by":"crossref","DOI":"10.7312\/nei-92038","volume-title":"Molecular Evolutionary Genetics","author":"Nei","year":"1987"},{"key":"2022010403442441000_R34","first-page":"418","article-title":"Simple methods for estimating the number of synonymous and nonsynonymous nucleotide substitutions","volume":"3","author":"Nei","year":"1986","journal-title":"Mol. Biol. Evol."},{"key":"2022010403442441000_R35","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1007\/s000360050019","article-title":"The ratio of replacement to silent divergence and tests of neutrality","volume":"10","author":"Nielsen","year":"1997","journal-title":"J. Evol. Biol."},{"key":"2022010403442441000_R36","doi-asserted-by":"crossref","first-page":"929","DOI":"10.1093\/genetics\/148.3.929","article-title":"Likelihood models for detecting positively selected amino acid sites and applications to the HIV-1 envelope gene","volume":"148","author":"Nielsen","year":"1998","journal-title":"Genetics"},{"key":"2022010403442441000_R37","doi-asserted-by":"crossref","first-page":"606","DOI":"10.1038\/375606a0","article-title":"Antigenic oscillations and shifting immunodominance in HIV-1 infections","volume":"375","author":"Nowak","year":"1995","journal-title":"Nature"},{"key":"2022010403442441000_R38","doi-asserted-by":"crossref","first-page":"1008","DOI":"10.1126\/science.274.5289.1008","article-title":"HIV-1 evolution and disease progression","volume":"274","author":"Nowak","year":"1996","journal-title":"Science"},{"key":"2022010403442441000_R39","doi-asserted-by":"crossref","first-page":"2103","DOI":"10.1126\/science.279.5359.2103","article-title":"Quantitation of HIV-1 specific cytotoxic T lymphocytes and plasma load of viral RNA","volume":"279","author":"Ogg","year":"1998","journal-title":"Science"},{"key":"2022010403442441000_R40","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1146\/annurev.es.23.110192.001403","article-title":"The nearly neutral theory of molecular evolution","volume":"23","author":"Ohta","year":"1992","journal-title":"Annu. Rev. Ecol. Syst."},{"key":"2022010403442441000_R41","doi-asserted-by":"crossref","first-page":"1582","DOI":"10.1126\/science.271.5255.1582","article-title":"HIV-1 dynamics in vivo: virion clearance rate, infected cell life-span, and viral generation time","volume":"271","author":"Perelson","year":"1996","journal-title":"Science"},{"key":"2022010403442441000_R42","doi-asserted-by":"crossref","first-page":"4233","DOI":"10.1128\/jvi.71.6.4233-4240.1997","article-title":"Genetic drift can determine short-term human immunodeficiency virus type 1 nef quasispecies evolution in vivo","volume":"71","author":"Plikat","year":"1997","journal-title":"J. Virol."},{"key":"2022010403442441000_R43","doi-asserted-by":"crossref","first-page":"1890","DOI":"10.1073\/pnas.94.5.1890","article-title":"Positive selection of HIV-1 cytotoxic T lymphocyte escape variants during primary infection","volume":"94","author":"Price","year":"1997","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2022010403442441000_R44","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1038\/30989","article-title":"A conditioned dendritic cell can be a temporal bridge between a CD4+ T-helper and a T-killer cell","volume":"393","author":"Ridge","year":"1998","journal-title":"Nature"},{"key":"2022010403442441000_R45","doi-asserted-by":"crossref","first-page":"1447","DOI":"10.1126\/science.278.5342.1447","article-title":"Vigorous HIV-1-specific CD4+ T cell responses associated with control of viremia","volume":"278","author":"Rosenberg","year":"1997","journal-title":"Science"},{"key":"2022010403442441000_R46","doi-asserted-by":"crossref","first-page":"7184","DOI":"10.1073\/pnas.91.15.7184","article-title":"Intensity of natural selection at the major histocompatibility complex loci","volume":"91","author":"Satta","year":"1994","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2022010403442441000_R47","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1126\/science.283.5403.857","article-title":"Control of viremia in simian immunodeficiency virus infection by CD8+ lymphocytes","volume":"283","author":"Schmitz","year":"1999","journal-title":"Science"},{"key":"2022010403442441000_R48","doi-asserted-by":"crossref","first-page":"480","DOI":"10.1038\/31002","article-title":"T-cell help for cytotoxic T lymphocytes is mediated by CD40-CD40L interactions","volume":"393","author":"Schoenberger","year":"1998","journal-title":"Nature"},{"key":"2022010403442441000_R49","first-page":"111","article-title":"In search of molecular Darwinism","volume":"385","author":"Sharp","year":"1997","journal-title":"Nature"},{"key":"2022010403442441000_R50","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1093\/oso\/9780195074444.003.0020","article-title":"The high rate of retrovirus variation results in rapid evolution","volume-title":"Emerging Viruses","author":"Temin","year":"1993"},{"key":"2022010403442441000_R51","doi-asserted-by":"crossref","first-page":"4673","DOI":"10.1093\/nar\/22.22.4673","article-title":"CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, positions-specific gap penalties and weight matrix choice","volume":"22","author":"Thompson","year":"1994","journal-title":"Nucleic Acids Res."},{"key":"2022010403442441000_R52","first-page":"185","article-title":"Is antigenic variation of HIV important for AIDS and what might be expected in the future?","volume-title":"The Evolutionary Biology of Viruses","author":"Wain-Hobson","year":"1994"},{"key":"2022010403442441000_R53","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/0966-842X(96)10023-8","article-title":"Running the gamut of retroviral variation","volume":"4","author":"Wain-Hobson","year":"1996","journal-title":"Trends Microbiol."},{"key":"2022010403442441000_R54","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1006\/viro.1996.0240","article-title":"Human immunodeficiency virus type 1 Nef protein is incorporated into virus particles and specifically cleaved by the viral proteinase","volume":"219","author":"Welker","year":"1996","journal-title":"Virology"},{"key":"2022010403442441000_R55","volume-title":"Phylogenetic Analysis by Maximum Likelihood (PAML)","author":"Yang","year":"1997"},{"key":"2022010403442441000_R56","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1146\/annurev.ecolsys.27.1.543","article-title":"Adaptive evolution of photoreceptors and visual pigments in vertebrates","volume":"27","author":"Yokohama","year":"1996","journal-title":"Annu. Rev. Ecol. Syst."},{"key":"2022010403442441000_R57","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1006\/viro.1995.1326","article-title":"An arbovirus cline across the Northern hemisphere","volume":"210","author":"Zanotto","year":"1995","journal-title":"Virology"}],"container-title":["Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/genetics\/article-pdf\/153\/3\/1077\/42025877\/genetics1077.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/genetics\/article-pdf\/153\/3\/1077\/42025877\/genetics1077.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,8,29]],"date-time":"2024-08-29T16:49:29Z","timestamp":1724950169000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/genetics\/article\/153\/3\/1077\/6050782"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[1999,11,1]]},"references-count":57,"journal-issue":{"issue":"3","published-online":{"date-parts":[[1999,11,1]]},"published-print":{"date-parts":[[1999,11,1]]}},"URL":"https:\/\/doi.org\/10.1093\/genetics\/153.3.1077","relation":{},"ISSN":["1943-2631"],"issn-type":[{"value":"1943-2631","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[1999,11,1]]},"published":{"date-parts":[[1999,11,1]]}}}