The contribution of viral genotype to plasma viral set-point in HIV infection

Abstract

Disease progression in HIV-infected individuals varies greatly, and while the environmental and host factors influencing this variation have been widely investigated, the viral contribution to variation in set-point viral load, a predictor of disease progression, is less clear. Previous studies, using transmission-pairs and analysis of phylogenetic signal in small numbers of individuals, have produced a wide range of viral genetic effect estimates. Here we present a novel application of a population-scale method based in quantitative genetics to estimate the viral genetic effect on set-point viral load in the UK subtype B HIV-1 epidemic, based on a very large data set. Analyzing the initial viral load and associated pol sequence, both taken before anti-retroviral therapy, of 8,483 patients, we estimate the proportion of variance in viral load explained by viral genetic effects to be 5.7% (CI 2.8-8.6%). We also estimated the change in viral load over time due to selection on the virus and environmental effects to be a decline of 0.05 log10 copies/mL/year, in contrast to recent studies which suggested a reported small increase in viral load over the last 20 years might be due to evolutionary changes in the virus. Our results suggest that in the UK epidemic, subtype B has a small but significant viral genetic effect on viral load. By allowing the analysis of large sample sizes, we expect our approach to be applicable to the estimation of the genetic contribution to traits in many organisms.

Figure 1. The estimated node effect plotted onto the phylogeny.

The estimated phylogenetic effect of each node on log₁₀ viral load plotted back onto the phylogeny from the 652-sample BEAST analysis. The axis shows the time in years from the most recent sequence, which was taken in 2009. Branches have been colored by the scale of the effect. Clusters of branches have been collapsed to improve readability, and are colored by the average tip effect within each cluster. As the number of bifurcations in the tree reduces at around 17.5 years before 2009, this used as the threshold for collapsing. Nodes that have a similar effect on viral load cluster together, as expected if some of the variation in viral load is heritable.

Figure 2. Change in viral load over time due to selection.

The estimated log₁₀ change in viral load per year due to selection and environmental effects (see also Fig. S2).