The genetic architecture of HIV-1 virulence
Blanquart F., Wymant C., Hall M., Power R., Golubchik T., Gall A., de Cesare M., Macintyre-Cockett G., Bakker M., Bezemer D., Gabrielaite M., Ong SH., Kendall M., Sauter R., Bannert N., Fellay J., Grabowski MK., Gunsenheimer-Bartmeyer B., Günthard HF., Kivelä P., Kouyos RD., Laeyendecker O., Marvig RL., Meixenberger K., Meyer L., van Sighem A., Bonsall D., van der Valk M., Berkhout B., Kellam P., Cornelissen M., Reiss P., Fraser C.
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 ${\log}_{10}$ 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.