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

Emma Hodcroft,Andrew Phillips,Esther Fearnhill,Deenan Pillay,David Dunn,Andrew J Leigh Brown,Siobhan O'Shea,Jarrod D Hadfield,Michael Worobey

doi:10.1371/journal.ppat.1004112

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.

Highlights

Plasma viral load has long been considered one of the most important clinical measures in HIV-positive patients
A lack of standardization of when measurements were taken, what measures were used, and whether patients were on anti-retroviral therapy (ART), as well as differences in the subtypes, risk groups, and demographics of the patients involved mean that these studies are difficult to compare directly
We have adapted a method from quantitative genetics which considers the viral phylogeny as a pedigree, permitting analysis of large cohort-derived datasets for the first time

Summary

Introduction

Plasma viral load has long been considered one of the most important clinical measures in HIV-positive patients. The progression time from infection to AIDS or death varies enormously from a few years to decades, and ‘set-point’ viral load, taken early in the asymptomatic phase of the disease, is the best known early predictor of the long-term rate of disease progression [1,2,3] and is strongly associated with transmission risk [4,5,6]. In the mid-1980’s, it became clear that some HIV isolates, deemed ‘high/fast’ lines, had a much higher replicative capacity in cell lines than others [16,17,18]. Two meta-analyses have been performed, both concluding that a decrease in CD4+ count and an increase in viral load can be observed, implying an increase in HIV virulence

Methods

Results

Conclusion