The genetic architecture of HIV-1 virulence.

Authors

François Blanquart, Chris Wymant, Matthew Hall, Robert Power, Tanya Golubchik, Astrid Gall, Mariateresa de Cesare, George Macintyre-Cockett, Margreet Bakker, Daniela Bezemer, Migle Gabrielaite, Swee Hoe Ong, Michelle Kendall, Rafael Sauter, Norbert Bannert, Jacques Fellay, M Kate Grabowski, Barbara Gunsenheimer-Bartmeyer, Huldrych F Günthard, Pia Kivelä, Roger D Kouyos, Oliver Laeyendecker, Rasmus L Marvig, Karolin Meixenberger, Laurence Meyer, Ard van Sighem, David Bonsall, Marc van der Valk, Ben Berkhout, Paul Kellam, Marion Cornelissen, Peter Reiss, Christophe Fraser

Published in

Virus evolution. Volume 11. Issue 1. Pages veaf057. Epub Dec 05, 2025.

Abstract

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 "Bridging the Evolution and Epidemiology of HIV in Europe" (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 months 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%-35%] of the variance in SPVL, while they explained only 0.9% [0.0%-2.1%] 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 -0.26 [Formula: see text] copies/ml and an epitope mutation allowing escape from the host HLA-B^*35 allele and increasing SPVL by +0.22 [Formula: see text] 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 (R ² 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.

PMID:
41368623
Bibliographic data and abstract were imported from PubMed on 10 Dec 2025.

Read full publication at:
Please sign in to see all details.

Stats

1-terrible, 9-excellent. How would you rate this publication? Sign in in to submit your rating.

Post a comment

You need to be signed in to post comments. You can sign in here.

Comments

There are no comments yet.