{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,8]],"date-time":"2025-12-08T17:55:11Z","timestamp":1765216511156,"version":"3.46.0"},"reference-count":74,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2025,12,5]],"date-time":"2025-12-05T00:00:00Z","timestamp":1764892800000},"content-version":"vor","delay-in-days":338,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,1,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The virulence of Human Immunodeficiency Virus-1 (HIV-1) is partly determined by viral genetic variation. Finding individual genetic variants affecting virulence is important for our understanding of HIV pathogenesis and evolution of virulence; however, very few have been identified. To this end, within the \u201cBridging the Evolution and Epidemiology of HIV in Europe\u201d (BEEHIVE) collaboration, we produced whole-genome HIV sequence data for 2294 seroconverters from European countries for a genome-wide association study (GWAS). We considered two phenotypes: (i) set-point viral load (SPVL), the approximately stable viral load from 6 to 24\u00a0months after infection, and (ii) the rate of CD4 cell count decline. We developed a GWAS method that corrects for population structure with random effects, accounts for two or more alleles at each locus, and tests for the effect of multiple genetic variants including single-nucleotide polymorphisms (SNPs), k-mers, insertions and deletions, within-host variant frequency, the number of rare point mutations, and drug resistance. We confirmed with this new approach that viral genomes explained 26% [95% CI 17%\u201335%] of the variance in SPVL, while they explained only 0.9% [0.0%\u20132.1%] of the variance in the rate of CD4 cell count decline. After correction for multiple testing, among all tested variants, only two significantly explained SPVL: an epitope mutation allowing escape from the host HLA-B*57 allele and lowering SPVL by \u22120.26 ${\\log}_{10}$ copies\/ml and an epitope mutation allowing escape from the host HLA-B*35 allele and increasing SPVL by +0.22 ${\\log}_{10}$ copies\/ml. We attempted to replicate these two large effects in two additional independent datasets together encompassing 2445 seroconverters, with mixed results. Overall, the inferred effects of all SNPs and amino-acid variants weakly correlated (R2 ranging from 0.08 to 0.87%, P-values from 0.001 to 0.32) between our main dataset and these two additional datasets. Lastly, a lasso regression of phenotypes on genetic variants confirmed the heritability of SPVL and explained up to 6% of variance in SPVL in cross-validation datasets. These findings suggest that HIV SPVL is determined by viral genomes through HLA escape variants with potentially large, host-dependent effects that may not always be detected at the population level and many other variants with effects too weak to reach genome-wide significance in our GWAS.<\/jats:p>","DOI":"10.1093\/ve\/veaf057","type":"journal-article","created":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T12:35:29Z","timestamp":1764592529000},"source":"Crossref","is-referenced-by-count":0,"title":["The genetic architecture of HIV-1 virulence"],"prefix":"10.1093","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0591-2466","authenticated-orcid":false,"given":"Fran\u00e7ois","family":"Blanquart","sequence":"first","affiliation":[{"name":"Center for Interdisciplinary Research in Biology, CNRS, Coll\u00e8ge de France, PSL Research University , 11 place Marcelin Berthelot, Paris 75231 ,","place":["France"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9847-8226","authenticated-orcid":false,"given":"Chris","family":"Wymant","sequence":"additional","affiliation":[{"name":"Pandemic Sciences Institute, Nuffield Department of Medicine, University of Oxford , Old Road Campus, Oxford OX3 7LF ,","place":["United Kingdom"]},{"name":"Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, Nuffield Department of Medicine, University of Oxford , Old Road Campus, Oxford OX3 7LF ,","place":["United Kingdom"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2671-3864","authenticated-orcid":false,"given":"Matthew","family":"Hall","sequence":"additional","affiliation":[{"name":"Pandemic Sciences Institute, Nuffield Department of Medicine, University of Oxford , Old Road Campus, Oxford OX3 7LF ,","place":["United Kingdom"]},{"name":"Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, Nuffield Department of Medicine, University of Oxford , Old Road Campus, Oxford OX3 7LF ,","place":["United Kingdom"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert","family":"Power","sequence":"additional","affiliation":[{"name":"Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, Nuffield Department of Medicine, University of Oxford , Old Road Campus, Oxford OX3 7LF ,","place":["United Kingdom"]},{"name":"St Edmund Hall, University of Oxford , Queen's Ln, Oxford OX1 4AR ,","place":["United Kingdom"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2765-9828","authenticated-orcid":false,"given":"Tanya","family":"Golubchik","sequence":"additional","affiliation":[{"name":"Sydney Infectious Diseases Institute, Faculty of Medicine and Health, University of Sydney ; Biomedical Building, 1 Central Avenue, Eveleigh, NSW 2015 ,","place":["Australia"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Astrid","family":"Gall","sequence":"additional","affiliation":[{"name":"EMBO , Meyerhofstrasse 1, 69117 Heidelberg ,","place":["Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mariateresa","family":"de Cesare","sequence":"additional","affiliation":[{"name":"Pandemic Sciences Institute, Nuffield Department of Medicine, University of Oxford , Old Road Campus, Oxford OX3 7LF ,","place":["United Kingdom"]},{"name":"Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, Nuffield Department of Medicine, University of Oxford , Old Road Campus, Oxford OX3 7LF ,","place":["United Kingdom"]},{"name":"Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford , Roosevelt Dr, Headington, Oxford OX3 7BN ,","place":["United Kingdom"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"George","family":"Macintyre-Cockett","sequence":"additional","affiliation":[{"name":"Pandemic Sciences Institute, Nuffield Department of Medicine, University of Oxford , Old Road Campus, Oxford OX3 7LF ,","place":["United Kingdom"]},{"name":"Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, Nuffield Department of Medicine, University of Oxford , Old Road Campus, Oxford OX3 7LF ,","place":["United Kingdom"]},{"name":"Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford , Roosevelt Dr, Headington, Oxford OX3 7BN ,","place":["United Kingdom"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Margreet","family":"Bakker","sequence":"additional","affiliation":[{"name":"Amsterdam University Medical Centers, University of Amsterdam, Medical Microbiology and Infection Prevention, Laboratory of Experimental Virology , Meibergdreef 9, 1105 AZ, Amsterdam ,","place":["The Netherlands"]},{"name":"Amsterdam institute for Immunology and Infectious diseases , Meibergdreef 9, 1105 AZ, Amsterdam ,","place":["The Netherlands"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniela","family":"Bezemer","sequence":"additional","affiliation":[{"name":"Stichting HIV Monitoring , Tafelbergweg 51, 1105 BD Amsterdam ,","place":["The Netherlands"]},{"name":"Department of Infectious Diseases, Amsterdam Institute for Immunology and Infectious Diseases, Amsterdam UMC, University of Amsterdam , Meibergdreef 9, 1105 AZ, Amsterdam ,","place":["The Netherlands"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7959-8767","authenticated-orcid":false,"given":"Migle","family":"Gabrielaite","sequence":"additional","affiliation":[{"name":"Institute of Biotechnology, Life Sciences Center, Vilnius University , Sauletekio al. 7, 10257 Vilnius ,","place":["Lithuania"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3629-5387","authenticated-orcid":false,"given":"Swee Hoe","family":"Ong","sequence":"additional","affiliation":[{"name":"Wellcome Sanger Institute, Wellcome Genome Campus , Hinxton, Cambridge CB10 1SA ,","place":["United Kingdom"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michelle","family":"Kendall","sequence":"additional","affiliation":[{"name":"Department of Statistics, University of Warwick , Coventry CV4 7AL, United Kingdom"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rafael","family":"Sauter","sequence":"additional","affiliation":[{"name":"Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, Nuffield Department of Medicine, University of Oxford , Old Road Campus, Oxford OX3 7LF ,","place":["United Kingdom"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Norbert","family":"Bannert","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Unit 18, Robert Koch Institute , Nordufer 20, 13353 Berlin ,","place":["Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8240-939X","authenticated-orcid":false,"given":"Jacques","family":"Fellay","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Ecole Polytechnique F\u00e9d\u00e9rale de Lausanne , Station 19, 1015 Lausanne ,","place":["Switzerland"]},{"name":"Precision Medicine Unit, Lausanne University Hospital and University of Lausanne , Rue du Bugnon 46, 1011 Lausanne ,","place":["Switzerland"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M Kate","family":"Grabowski","sequence":"additional","affiliation":[{"name":"Department of Pathology, Johns Hopkins School of Medicine , 446 Carnegie Building, 600 N Wolfe St, 21287 Baltimore MD ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Barbara","family":"Gunsenheimer-Bartmeyer","sequence":"additional","affiliation":[{"name":"Department of Infectious Disease Epidemiology, Unit 34 HIV\/AIDS, STI and Blood-borne infections, Robert Koch Institute , Nordufer 20, 13353 Berlin ,","place":["Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huldrych F","family":"G\u00fcnthard","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich , Raemistrasse 100, 8091 Zurich ,","place":["Switzerland"]},{"name":"Institute of Medical Virology, University of Zurich , Winterthurerstrasse 190, 8057 Zurich ,","place":["Switzerland"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pia","family":"Kivel\u00e4","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Helsinki University Hospital , 00029 HUS, Helsinki ,","place":["Finland"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roger D","family":"Kouyos","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich , Raemistrasse 100, 8091 Zurich ,","place":["Switzerland"]},{"name":"Institute of Medical Virology, University of Zurich , Winterthurerstrasse 190, 8057 Zurich ,","place":["Switzerland"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6429-4760","authenticated-orcid":false,"given":"Oliver","family":"Laeyendecker","sequence":"additional","affiliation":[{"name":"Division of Intramural Research, National Institute of Allergy and Infectious Diseases , 855 North Wolfe St, 21209 Baltimore, MD ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5267-3173","authenticated-orcid":false,"given":"Rasmus L","family":"Marvig","sequence":"additional","affiliation":[{"name":"Department of Genomic Medicine, Rigshospitalet , Blegdamsvej 9, 2100 Copenhagen ,","place":["Denmark"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6587-6394","authenticated-orcid":false,"given":"Karolin","family":"Meixenberger","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Unit 18 Sexually transmitted bacterial Pathogens (STI) and HIV, Robert Koch Institute , Seestrasse 10, 13353 Berlin ,","place":["Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laurence","family":"Meyer","sequence":"additional","affiliation":[{"name":"Inserm CESP U1018, APHP Bicetre Hospital, Paris Saclay University , 82 rue du general Leclerc, 94276 le Kremlin-Bicetre ,","place":["France"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ard","family":"van Sighem","sequence":"additional","affiliation":[{"name":"Stichting HIV Monitoring , Tafelbergweg 51, 1105 BD Amsterdam ,","place":["The Netherlands"]},{"name":"Department of Infectious Diseases, Amsterdam Institute for Immunology and Infectious Diseases, Amsterdam UMC, University of Amsterdam , Meibergdreef 9, 1105 AZ, Amsterdam ,","place":["The Netherlands"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David","family":"Bonsall","sequence":"additional","affiliation":[{"name":"Pandemic Sciences Institute, Nuffield Department of Medicine, University of Oxford , Old Road Campus, Oxford OX3 7LF ,","place":["United Kingdom"]},{"name":"Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, Nuffield Department of Medicine, University of Oxford , Old Road Campus, Oxford OX3 7LF ,","place":["United Kingdom"]},{"name":"Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford , Roosevelt Dr, Headington, Oxford OX3 7BN ,","place":["United Kingdom"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marc","family":"van der Valk","sequence":"additional","affiliation":[{"name":"Stichting HIV Monitoring , Tafelbergweg 51, 1105 BD Amsterdam ,","place":["The Netherlands"]},{"name":"Department of Infectious Diseases, Amsterdam Institute for Immunology and Infectious Diseases, Amsterdam UMC, University of Amsterdam , Meibergdreef 9, 1105 AZ, Amsterdam ,","place":["The Netherlands"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ben","family":"Berkhout","sequence":"additional","affiliation":[{"name":"Laboratory of Experimental Virology, Department of Medical Microbiology, Amsterdam University Medical Centers, University of Amsterdam , Meibergdreef 15, 1105 AZ, Amsterdam ,","place":["The Netherlands"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3166-4734","authenticated-orcid":false,"given":"Paul","family":"Kellam","sequence":"additional","affiliation":[{"name":"Department of Infectious Disease, South Kensington Campus, Imperial College London , London, SW7 2AZ ,","place":["United Kingdom"]},{"name":"RQ Biotechnology Ltd , London, Scale Space, 58 Wood Lane, London, W12 7RZ ,","place":["United Kingdom"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marion","family":"Cornelissen","sequence":"additional","affiliation":[{"name":"Medical Microbiology and Infection Prevention, Laboratory of Clinical Virology, Amsterdam University Medical Centers , Meibergdreef 9, 1105 AZ, Amsterdam ,","place":["The Netherlands"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7896-6428","authenticated-orcid":false,"given":"Peter","family":"Reiss","sequence":"additional","affiliation":[{"name":"Amsterdam University Medical Center, University of Amsterdam, Global Health, Amsterdam institute for Immunology and Infectious diseases and Amsterdam Institute for Global Health and Development , Meibergdreef 9, 1105 AZ Amsterdam ,","place":["The Netherlands"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christophe","family":"Fraser","sequence":"additional","affiliation":[{"name":"Pandemic Sciences Institute, Nuffield Department of Medicine, University of Oxford , Old Road Campus, Oxford OX3 7LF ,","place":["United Kingdom"]},{"name":"Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, Nuffield Department of Medicine, University of Oxford , Old Road Campus, Oxford OX3 7LF ,","place":["United Kingdom"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2025,12,5]]},"reference":[{"key":"2025120812520415000_ref1","doi-asserted-by":"crossref","first-page":"e1001123","DOI":"10.1371\/journal.ppat.1001123","article-title":"Phylogenetic approach reveals that virus genotype largely determines HIV set-point viral load","volume":"6","author":"Alizon","year":"2010","journal-title":"PLoS Pathog"},{"key":"2025120812520415000_ref2","doi-asserted-by":"crossref","first-page":"660","DOI":"10.1016\/S0140-6736(86)90169-8","article-title":"Replicative capacity of human immunodeficiency virus from patients with varying severity of HIV infection","volume":"2","author":"Asj\u00f6","year":"1986","journal-title":"Lancet (London, England)"},{"key":"2025120812520415000_ref3","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1186\/s12977-017-0356-3","article-title":"Parent-offspring regression to estimate the heritability of an HIV-1 trait in a realistic setup","volume":"14","author":"Bachmann","year":"2017","journal-title":"Retrovirology"},{"key":"2025120812520415000_ref4","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1089\/cmb.2012.0021","article-title":"SPAdes: A new genome assembly algorithm and its applications to single-cell sequencing","volume":"19","author":"Bankevich","year":"2012","journal-title":"J Comput Biol"},{"key":"2025120812520415000_ref5","doi-asserted-by":"crossref","first-page":"e01123","DOI":"10.7554\/eLife.01123","article-title":"A genome-to-genome analysis of associations between human genetic variation, HIV-1 sequence diversity, and viral control","volume":"2","author":"Bartha","year":"2013","journal-title":"elife"},{"key":"2025120812520415000_ref6","doi-asserted-by":"crossref","first-page":"e1005339","DOI":"10.1371\/journal.pcbi.1005339","article-title":"Estimating the respective contributions of human and viral genetic variation to HIV control","volume":"13","author":"Bartha","year":"2017","journal-title":"PLoS Comput Biol"},{"key":"2025120812520415000_ref7","doi-asserted-by":"crossref","DOI":"10.1214\/20-AOAS1419","article-title":"Efficient bayesian inference of general gaussian models on large phylogenetic trees","volume-title":"The Annals of Applied Statistics","author":"Bastide"},{"key":"2025120812520415000_ref8","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1093\/molbev\/msx246","article-title":"Dissecting HIV virulence: Heritability of setpoint viral load, CD4+ T-cell decline, and per-parasite pathogenicity","volume":"35","author":"Bertels","year":"2018","journal-title":"Mol Biol Evol"},{"key":"2025120812520415000_ref10","doi-asserted-by":"crossref","first-page":"e2001855","DOI":"10.1371\/journal.pbio.2001855","article-title":"Viral genetic variation accounts for a third of variability in HIV-1 set-point viral load in Europe","volume":"15","author":"Blanquart","year":"2017","journal-title":"PLoS Biol"},{"key":"2025120812520415000_ref11","doi-asserted-by":"publisher","DOI":"10.1128\/jcm.00382-20","article-title":"A comprehensive genomics solution for HIV surveillance and clinical monitoring in low-income settings","volume":"58","author":"Bonsall","year":"2020","journal-title":"J Clin Microbiol"},{"key":"2025120812520415000_ref12","doi-asserted-by":"publisher","first-page":"13202","DOI":"10.1128\/JVI.01998-12","article-title":"Correlates of protective cellular immunity revealed by analysis of population-level immune escape pathways in HIV-1","volume":"86","author":"Carlson","year":"2012","journal-title":"J Virol"},{"key":"2025120812520415000_ref13","doi-asserted-by":"publisher","first-page":"1254031","DOI":"10.1126\/science.1254031","article-title":"HIV transmission. Selection bias at the heterosexual HIV-1 transmission bottleneck","volume":"345","author":"Carlson","year":"2014","journal-title":"Science (New York, NY)"},{"key":"2025120812520415000_ref14","doi-asserted-by":"publisher","first-page":"s13742-015-0047-8","DOI":"10.1186\/s13742-015-0047-8","article-title":"Second-generation PLINK: Rising to the challenge of larger and richer datasets","volume":"4","author":"Chang","year":"2015","journal-title":"GigaScience"},{"key":"2025120812520415000_ref15","doi-asserted-by":"publisher","first-page":"e388","DOI":"10.1016\/S2352-3018(16)30034-0","article-title":"Heterogeneity of the HIV epidemic in agrarian, trading, and fishing communities in Rakai, Uganda: An observational epidemiological study","volume":"3","author":"Chang","year":"2016","journal-title":"Lancet HIV"},{"key":"2025120812520415000_ref16","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1007\/978-1-4939-7683-6_5","article-title":"Workup of human blood samples for deep sequencing of HIV-1 genomes","volume":"1746","author":"Cornelissen","year":"2018","journal-title":"Methods Mol Biol"},{"key":"2025120812520415000_ref17","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1097\/00002030-200203290-00009","article-title":"Determinants of recurrent toxicity-driven switches of highly active antiretroviral therapy. The ATHENA cohort","volume":"16","author":"Dieleman","year":"2002","journal-title":"AIDS"},{"key":"2025120812520415000_ref18","doi-asserted-by":"crossref","first-page":"e1003899","DOI":"10.1371\/journal.pcbi.1003899","article-title":"Immuno-epidemiological modeling of HIV-1 predicts high heritability of the set-point virus load, while selection for CTL escape dominates virulence evolution","volume":"10","author":"van Dorp","year":"2014","journal-title":"PLoS Comput Biol"},{"key":"2025120812520415000_ref19","doi-asserted-by":"crossref","first-page":"e1000791","DOI":"10.1371\/journal.pgen.1000791","article-title":"Common genetic variation and the control of HIV-1 in humans","volume":"5","author":"Fellay","year":"2009","journal-title":"PLoS Genet"},{"key":"2025120812520415000_ref20","doi-asserted-by":"crossref","first-page":"944","DOI":"10.1126\/science.1143767","article-title":"A whole-genome association study of major determinants for host control of HIV-1","volume":"317","author":"Fellay","year":"2007","journal-title":"Science"},{"key":"2025120812520415000_ref21","doi-asserted-by":"crossref","DOI":"10.2172\/1458915","volume-title":"HIV Sequence Compendium 2018","author":"Foley","year":"2018"},{"key":"2025120812520415000_ref22","doi-asserted-by":"crossref","first-page":"17441","DOI":"10.1073\/pnas.0708559104","article-title":"Variation in HIV-1 set-point viral load: Epidemiological analysis and an evolutionary hypothesis","volume":"104","author":"Fraser","year":"2007","journal-title":"Proc Natl Acad Sci"},{"key":"2025120812520415000_ref23","doi-asserted-by":"crossref","DOI":"10.1126\/science.1243727","article-title":"Virulence and pathogenesis of HIV-1 infection: An evolutionary perspective","volume":"343","author":"Fraser","year":"2014","journal-title":"Science"},{"key":"2025120812520415000_ref24","doi-asserted-by":"crossref","first-page":"e1001196","DOI":"10.1371\/journal.ppat.1001196","article-title":"Modelling the evolution and spread of HIV immune escape mutants","volume":"6","author":"Fryer","year":"2010","journal-title":"PLoS Pathog"},{"key":"2025120812520415000_ref25","doi-asserted-by":"crossref","first-page":"2053","DOI":"10.1093\/infdis\/jiab253","article-title":"Human immunotypes impose selection on viral genotypes through viral epitope specificity","volume":"224","author":"Gabrielaite","year":"2021","journal-title":"J Infect Dis"},{"key":"2025120812520415000_ref26","doi-asserted-by":"crossref","first-page":"3838","DOI":"10.1128\/JCM.01516-12","article-title":"Universal amplification, next-generation sequencing, and assembly of HIV-1 genomes","volume":"50","author":"Gall","year":"2012","journal-title":"J Clin Microbiol"},{"key":"2025120812520415000_ref28","doi-asserted-by":"publisher","first-page":"2862","DOI":"10.1093\/jac\/dkx247","article-title":"CD4 T cell decline following HIV seroconversion in individuals with and without CXCR4-tropic virus","volume":"72","author":"Ghosn","year":"2017","journal-title":"J Antimicrob Chemother"},{"key":"2025120812520415000_ref29","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1038\/35085576","article-title":"Evolution and transmission of stable CTL escape mutations in HIV infection","volume":"412","author":"Goulder","year":"2001","journal-title":"Nature"},{"key":"2025120812520415000_ref30","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1097\/00002030-200203290-00017","article-title":"Genotypic drug resistance during HIV-1 primary infection in France (1996\u20131999): Frequency and response to treatment","volume":"16","author":"Harzic","year":"2002","journal-title":"AIDS"},{"key":"2025120812520415000_ref31","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1097\/QAD.0b013e32834db418","article-title":"Is the virulence of HIV changing? A meta-analysis of trends in prognostic markers of HIV disease progression and transmission","volume":"26","author":"Herbeck","year":"2012","journal-title":"AIDS"},{"year":"..","author":"HIV Databases","key":"2025120812520415000_ref32"},{"key":"2025120812520415000_ref33","doi-asserted-by":"crossref","first-page":"e1004112","DOI":"10.1371\/journal.ppat.1004112","article-title":"The contribution of viral genotype to plasma viral set-point in HIV infection","volume":"10","author":"Hodcroft","year":"2014","journal-title":"PLoS Pathog"},{"key":"2025120812520415000_ref34","doi-asserted-by":"crossref","first-page":"2374","DOI":"10.1093\/bioinformatics\/btv120","article-title":"IVA: Accurate de novo assembly of RNA virus genomes","volume":"31","author":"Hunt","year":"2015","journal-title":"Bioinformatics"},{"key":"2025120812520415000_ref35","doi-asserted-by":"publisher","first-page":"1139","DOI":"10.1038\/nm.3932","article-title":"HIV-1 infections with multiple founders are associated with higher viral loads than infections with single founders","volume":"21","author":"Janes","year":"2015","journal-title":"Nat Med"},{"volume-title":"The Path that Ends AIDS: 2023 UNAIDS Global AIDS Update","year":"2023","author":"Joint United Nations Programme on HIV\/AIDS (UNAIDS)","key":"2025120812520415000_ref36"},{"key":"2025120812520415000_ref37","doi-asserted-by":"publisher","first-page":"1244","DOI":"10.1086\/340130","article-title":"Effect of human immunodeficiency virus (HIV) type 1 envelope subtypes A and D on disease progression in a large cohort of HIV-1-positive persons in Uganda","volume":"185","author":"Kaleebu","year":"2002","journal-title":"J Infect Dis"},{"key":"2025120812520415000_ref38","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1097\/00002030-200102160-00001","article-title":"Relationship between HIV-1 env subtypes A and D and disease progression in a rural Ugandan cohort","volume":"15","author":"Kaleebu","year":"2001","journal-title":"AIDS"},{"key":"2025120812520415000_ref39","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1038\/nm0496-405","article-title":"Influence of combinations of human major histocompatibility complex genes on the course of HIV-1 infection","volume":"2","author":"Kaslow","year":"1996","journal-title":"Nat Med"},{"key":"2025120812520415000_ref40","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1080\/00365540410021054","article-title":"High plasma HIV load in the CRF01-AE outbreak among injecting drug users in Finland","volume":"37","author":"Kivel\u00e4","year":"2005","journal-title":"Scand J Infect Dis"},{"key":"2025120812520415000_ref41","doi-asserted-by":"crossref","first-page":"681","DOI":"10.7326\/0003-4819-118-9-199305010-00004","article-title":"Prognostic value of HIV-1 syncytium-inducing phenotype for rate of CD4+ cell depletion and progression to AIDS","volume":"118","author":"Koot","year":"1993","journal-title":"Ann Intern Med"},{"key":"2025120812520415000_ref42","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1016\/j.ebiom.2015.01.015","article-title":"CRF19_cpx is an evolutionary fit HIV-1 variant strongly associated with rapid progression to AIDS in Cuba","volume":"2","author":"Kouri","year":"2015","journal-title":"EBioMedicine"},{"key":"2025120812520415000_ref43","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1186\/1742-4690-4-67","article-title":"Identifying HIV-1 dual infections","volume":"4","author":"van der Kuyl","year":"2007","journal-title":"Retrovirology"},{"key":"2025120812520415000_ref44","doi-asserted-by":"crossref","first-page":"1715","DOI":"10.1056\/NEJM199906033402203","article-title":"Immunologic and virologic status after 14 to 18 years of infection with an attenuated strain of HIV-1\u2014A report from the Sydney blood Bank cohort","volume":"340","author":"Learmont","year":"1999","journal-title":"N Engl J Med"},{"key":"2025120812520415000_ref45","doi-asserted-by":"publisher","first-page":"4310","DOI":"10.1093\/bioinformatics\/bty539","article-title":"Pyseer: A comprehensive tool for microbial pangenome-wide association studies","volume":"34","author":"Lees","year":"2018","journal-title":"Bioinformatics"},{"key":"2025120812520415000_ref46","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1038\/nm992","article-title":"HIV evolution: CTL escape mutation and reversion after transmission","volume":"10","author":"Leslie","year":"2004","journal-title":"Nat Med"},{"volume-title":"Linear Mixed Models for Genome-Wide Association Studies","year":"2013","author":"Lippert","key":"2025120812520415000_ref47"},{"key":"2025120812520415000_ref49","doi-asserted-by":"publisher","DOI":"10.1101\/2025.05.12.653435","article-title":"Attenuation of HIV severity by slightly deleterious mutations can explain the long-term trajectory of virulence evolution","author":"Longley","year":"2025","journal-title":"bioRxiv"},{"key":"2025120812520415000_ref50","doi-asserted-by":"publisher","first-page":"2462","DOI":"10.1093\/bioinformatics\/btq467","article-title":"RDP3: A flexible and fast computer program for analyzing recombination","volume":"26","author":"Martin","year":"2010","journal-title":"Bioinformatics"},{"key":"2025120812520415000_ref51","doi-asserted-by":"crossref","first-page":"866","DOI":"10.1016\/S0140-6736(98)04158-0","article-title":"CCR5 promoter polymorphism and HIV-1 disease progression. Multicenter AIDS cohort study (MACS)","volume":"352","author":"McDermott","year":"1998","journal-title":"Lancet"},{"key":"2025120812520415000_ref52","doi-asserted-by":"publisher","first-page":"1530","DOI":"10.1093\/molbev\/msaa015","article-title":"IQ-TREE 2: New models and efficient methods for phylogenetic inference in the genomic era","volume":"37","author":"Minh","year":"2020","journal-title":"Mol Biol Evol"},{"key":"2025120812520415000_ref53","doi-asserted-by":"crossref","first-page":"756","DOI":"10.1093\/molbev\/msx328","article-title":"A practical guide to estimating the heritability of pathogen traits","volume":"35","author":"Mitov","year":"2018","journal-title":"Mol Biol Evol"},{"key":"2025120812520415000_ref54","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1093\/infdis\/jit416","article-title":"Faster progression to AIDS and AIDS-related death among seroincident individuals infected with recombinant HIV-1 A3\/CRF02_AG compared with sub-subtype A3","volume":"209","author":"Palm","year":"2014","journal-title":"J Infect Dis"},{"key":"2025120812520415000_ref55","doi-asserted-by":"publisher","first-page":"589","DOI":"10.1016\/j.cell.2019.08.051","article-title":"Genome-wide association studies in ancestrally diverse populations: Opportunities, methods, pitfalls, and recommendations","volume":"179","author":"Peterson","year":"2019","journal-title":"Cell"},{"key":"2025120812520415000_ref56","doi-asserted-by":"publisher","first-page":"511","DOI":"10.1111\/j.1468-1293.2007.00504.x","article-title":"Impact of transmission of drug-resistant HIV on the course of infection and the treatment success. Data from the German HIV-1 Seroconverter study","volume":"8","author":"Poggensee","year":"2007","journal-title":"HIV Med"},{"key":"2025120812520415000_ref57","article-title":"SMALT-a new mapper for DNA sequencing reads","volume":"1","author":"Ponstingl","year":"2010","journal-title":"F1000 Posters"},{"key":"2025120812520415000_ref58","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1038\/nrg.2016.132","article-title":"Microbial genome-wide association studies: Lessons from human GWAS","volume":"18","author":"Power","year":"2017","journal-title":"Nat Rev Genet"},{"key":"2025120812520415000_ref59","doi-asserted-by":"publisher","first-page":"622","DOI":"10.1016\/S1473-3099(13)70066-5","article-title":"Frequency and implications of HIV superinfection","volume":"13","author":"Redd","year":"2013","journal-title":"Lancet Infect Dis"},{"key":"2025120812520415000_ref60","doi-asserted-by":"publisher","first-page":"1057","DOI":"10.1093\/infdis\/jiac100","article-title":"The interplay between replication capacity of HIV-1 and surrogate markers of disease","volume":"226","author":"Rindler","year":"2022","journal-title":"J Infect Dis"},{"key":"2025120812520415000_ref61","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1093\/ije\/dyab141","article-title":"Cohort profile update: The Swiss HIV cohort study (SHCS)","volume":"51","author":"Scherrer","year":"2022","journal-title":"Int J Epidemiol"},{"key":"2025120812520415000_ref62","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.887760","article-title":"Human Pegivirus type 1: A common human virus that is beneficial in immune-mediated disease?","volume":"13","author":"Stapleton","year":"2022","journal-title":"Front Immunol"},{"key":"2025120812520415000_ref63","doi-asserted-by":"crossref","first-page":"e144","DOI":"10.1093\/nar\/gku739","article-title":"COMET: Adaptive context-based modeling for ultrafast HIV-1 subtype identification","volume":"42","author":"Struck","year":"2014","journal-title":"Nucleic Acids Res"},{"volume-title":"Typewriter","year":"2018","author":"Golubchik T","key":"2025120812520415000_ref65"},{"key":"2025120812520415000_ref66","doi-asserted-by":"publisher","first-page":"1590","DOI":"10.1056\/NEJMra0706737","article-title":"The challenge of HIV-1 subtype diversity","volume":"358","author":"Taylor","year":"2008","journal-title":"N Engl J Med"},{"key":"2025120812520415000_ref67","doi-asserted-by":"publisher","first-page":"888","DOI":"10.1093\/cid\/cis1000","article-title":"Impact of HIV-1 subtype on CD4 count at HIV seroconversion, rate of decline, and viral load set point in European seroconverter cohorts","volume":"56","author":"Touloumi","year":"2013","journal-title":"Clin Infect Dis"},{"key":"2025120812520415000_ref68","doi-asserted-by":"publisher","first-page":"5513","DOI":"10.4049\/jimmunol.178.9.5513","article-title":"Altering effects of antigenic variations in HIV-1 on antiviral effectiveness of HIV-specific CTLs","volume":"178","author":"Ueno","year":"2007","journal-title":"J Immunol"},{"key":"2025120812520415000_ref69","doi-asserted-by":"crossref","first-page":"1107","DOI":"10.4049\/jimmunol.180.2.1107","article-title":"CTL-mediated selective pressure influences dynamic evolution and pathogenic functions of HIV-1 Nef","volume":"180","author":"Ueno","year":"2008","journal-title":"J Immunol"},{"key":"2025120812520415000_ref70","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1017\/S0950268800001485","article-title":"The UK register of HIV Seroconverters: Methods and analytical issues","volume":"117","author":"UK Register of HIV Seroconverters (UKRHS) Steering Committee","year":"1996","journal-title":"Epidemiol Infect"},{"key":"2025120812520415000_ref71","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1038\/373117a0","article-title":"Viral dynamics in human immunodeficiency virus type 1 infection","volume":"373","author":"Wei","year":"1995","journal-title":"Nature"},{"key":"2025120812520415000_ref72","first-page":"132","article-title":"2015 update of the drug resistance mutations in HIV-1","volume":"23","author":"Wensing","year":"2015","journal-title":"Top Antivir Med"},{"key":"2025120812520415000_ref73","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/gb-2014-15-3-r46","article-title":"Kraken: Ultrafast metagenomic sequence classification using exact alignments","volume":"15","author":"Wood","year":"2014","journal-title":"Genome Biol"},{"key":"2025120812520415000_ref74","doi-asserted-by":"publisher","first-page":"540","DOI":"10.1126\/science.abk1688","article-title":"A highly virulent variant of HIV-1 circulating in the Netherlands","volume":"375","author":"Wymant","year":"2022","journal-title":"Science"},{"key":"2025120812520415000_ref75","doi-asserted-by":"crossref","first-page":"vey007","DOI":"10.1093\/ve\/vey007","article-title":"Easy and accurate reconstruction of whole HIV genomes from short-read sequence data with shiver","volume":"4","author":"Wymant","year":"2018","journal-title":"Virus Evol"},{"key":"2025120812520415000_ref76","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1093\/molbev\/msx304","article-title":"PHYLOSCANNER: Inferring transmission from within-and between-host pathogen genetic diversity","volume":"35","author":"Wymant","year":"2018","journal-title":"Mol Biol Evol"},{"key":"2025120812520415000_ref77","doi-asserted-by":"crossref","first-page":"e1004722","DOI":"10.1371\/journal.ppat.1004722","article-title":"Persistence of transmitted HIV-1 drug resistance mutations associated with fitness costs and viral genetic backgrounds","volume":"11","author":"Yang","year":"2015","journal-title":"PLoS Pathog"},{"key":"2025120812520415000_ref79","doi-asserted-by":"crossref","first-page":"veac022","DOI":"10.1093\/ve\/veac022","article-title":"Phylogenetic estimation of the viral fitness landscape of HIV-1 set-point viral load","volume":"8","author":"Zhao","year":"2022","journal-title":"Virus Evol"}],"container-title":["Virus Evolution"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/ve\/advance-article-pdf\/doi\/10.1093\/ve\/veaf057\/65778725\/veaf057.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/ve\/article-pdf\/11\/1\/veaf057\/65778725\/veaf057.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/ve\/article-pdf\/11\/1\/veaf057\/65778725\/veaf057.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,8]],"date-time":"2025-12-08T17:52:14Z","timestamp":1765216334000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/ve\/article\/doi\/10.1093\/ve\/veaf057\/8371791"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025]]},"references-count":74,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2025,1,9]]}},"URL":"https:\/\/doi.org\/10.1093\/ve\/veaf057","relation":{},"ISSN":["2057-1577"],"issn-type":[{"type":"electronic","value":"2057-1577"}],"subject":[],"published-other":{"date-parts":[[2025]]},"published":{"date-parts":[[2025]]},"article-number":"veaf057"}}