Viral genetic variation accounts for a third of variability in HIV-1 set-point viral load in Europe

Blanquart, François; Wymant, Chris; Cornelissen, Marion; Gall, Astrid; Bakker, Margreet; Bezemer, Daniela; Hall, Matthew; Hillebregt, Mariska; Ong, Swee Hoe; Albert, Jan; Bannert, Norbert; Fellay, Jacques; Fransen, Katrien; Gourlay, Annabelle; Grabowski, M Kate; Gunsenheimer‐Bartmeyer, Barbara; Günthard, Huldrych F.; Kivelä, Pia; Kouyos, Roger D.; Laeyendecker, Oliver; Liitsola, Kirsi; Meyer, Laurence; Porter, Kholoud; Ristola, Matti; Sighem, Ard van; Vanham, Guido; Berkhout, Ben; Kellam, Paul; Reiss, Peter; Fraser, Christophe

doi:10.1371/journal.pbio.2001855

Cited by 47 publications

(83 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Our study confirms previous studies that established the heritability of the set-point viral load in HIV infection (as reviewed by Müller et al (2011) andFraser et al (2014)). In particular, our estimates are consistent with those from a donor-recipient regression in Hollingsworth et al (2010), and two recent studies applying phylogenetic mixed models based on the Ornstein-Uhlenbeck process by Mitov and Stadler (2016) and Blanquart et al (2017). Our analysis is also consistent with the study by Hodcroft et al (2014) that reported a low heritability of 5.7% of the set-point viral load adjusted for covariates and assuming Brownian trait evolution.…”

Section: Discussionsupporting

confidence: 89%

See 1 more Smart Citation

Dissecting HIV Virulence: Heritability of Setpoint Viral Load, CD4+ T Cell Decline and Per-Parasite Pathogenicity

Bertels

Marzel

Leventhal

et al. 2017

Preprint

Self Cite

View full text Add to dashboard Cite

Pathogen strains may differ in virulence because they attain different loads in their hosts, or because they induce different disease-causing mechanisms independent of their load. In evolutionary ecology, the latter is referred to as "per-parasite pathogenicity". Using viral load and CD4þ T-cell measures from 2014 HIV-1 subtype B-infected individuals enrolled in the Swiss HIV Cohort Study, we investigated if virulence-measured as the rate of decline of CD4þ T cells-and per-parasite pathogenicity are heritable from donor to recipient. We estimated heritability by donor-recipient regressions applied to 196 previously identified transmission pairs, and by phylogenetic mixed models applied to a phylogenetic tree inferred from HIV pol sequences. Regressing the CD4þ T-cell declines and perparasite pathogenicities of the transmission pairs did not yield heritability estimates significantly different from zero. With the phylogenetic mixed model, however, our best estimate for the heritability of the CD4þ T-cell decline is 17% (5-30%), and that of the per-parasite pathogenicity is 17% (4-29%). Further, we confirm that the set-point viral load is heritable, and estimate a heritability of 29% (12-46%). Interestingly, the pattern of evolution of all these traits differs significantly from neutrality, and is most consistent with stabilizing selection for the set-point viral load, and with directional selection for the CD4þ T-cell decline and the per-parasite pathogenicity. Our analysis shows that the viral genotype affects virulence mainly by modulating the per-parasite pathogenicity, while the indirect effect via the set-point viral load is minor.

show abstract

Section: Discussionsupporting

confidence: 89%

“…The recent study by Blanquart et al (2017) also reports heritability of the CD4+ T cell decline. For the HIV-1 subtype B, they estimate a heritability of 11% ranging from 0% to 19%.…”

Section: Discussionmentioning

confidence: 89%

Dissecting HIV Virulence: Heritability of Setpoint Viral Load, CD4+ T Cell Decline and Per-Parasite Pathogenicity

Bertels

Marzel

Leventhal

et al. 2017

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…Importantly, viral genetic variation may play a more important role in shaping HIV virulence than host factors, with approximately one-third of the observed variability in SPVL assigned to virus factors 111 and only ~13% seemingly due to the host 112 . This observation also implies that SPVL, and hence virulence, can be selectively optimized 113 .…”

Section: Subtype Of Influenza Virusmentioning

confidence: 99%

“…Importantly, however, despite many studies into the determinants of HIV virulence, the virus genomic mutations responsible for determining SPVL are still uncertain and multiple genes may be involved 104 . The difficulty in assigning the genetic determinants of SPVL may be in part due to genetic variation across viral populations 111 . For example, heritability in SPVL was highest (~60%) between individuals in the Swiss HIV cohort, which also represents the most homogenous viral population 113 .…”

Section: Subtype Of Influenza Virusmentioning

confidence: 99%

The phylogenomics of evolving virus virulence

2018

View full text Add to dashboard Cite

| How virulence evolves after a virus jumps to a new host species is central to disease emergence. Our current understanding of virulence evolution is based on insights drawn from two perspectives that have developed largely independently: long-standing evolutionary theory based on limited real data examples that often lack a genomic basis, and experimental studies of virulence-determining mutations using cell culture or animal models. A more comprehensive understanding of virulence mutations and their evolution can be achieved by bridging the gap between these two research pathways through the phylogenomic analysis of virus genome sequence data as a guide to experimental study.

show abstract

“…Large-scale sequencing of HIV genomes with NGS using overlapping 2-3 kb PCR amplicons [9] has been used to produce complete genomes for European samples [10], but the method's performance was found to be far from optimal on sub-Saharan African samples, with amplification failures resulting in biased genome coverage [11]. In our previously reported protocol, veSEQ, for Hepatitis C Virus (HCV), a virus which is even more diverse than HIV, we avoided such a genotype-dependent failure rate by avoiding virus-specific PCR altogether [12].…”

Section: Introductionmentioning

confidence: 99%

A comprehensive genomics solution for HIV surveillance and clinical monitoring in a global health setting

Bonsall

Golubchik

Cesare

et al. 2018

Preprint

Self Cite

View full text Add to dashboard Cite

High-throughput viral genetic sequencing is needed to monitor the spread of drug resistance, direct optimal antiretroviral regimes, and to identify transmission dynamics in generalised HIV epidemics. Public health efforts to sequence HIV genomes at scale face three major technical challenges: (i) minimising assay cost and protocol complexity, (ii) maximising sensitivity, and (iii) recovering accurate and unbiased sequences of both the genome consensus and the within-host viral diversity. Here we present a novel, high-throughput, virus-enriched sequencing method and computational pipeline tailored specifically to HIV (veSEQ-HIV), which addresses all three technical challenges, and can be used directly on leftover blood drawn for routine CD4 testing. We demonstrate its performance on 1,620 plasma samples collected from consenting individuals attending 10 large urban clinics in Zambia, partners of HPTN 071 (PopART). We show that veSEQ-HIV consistently recovers complete HIV genomes from the majority of samples of different subtypes, and is also quantitative: the number of HIV reads per sample obtained by veSEQ-HIV estimates viral load without the need for additional testing. Both quantitativity and sensitivity were assessed on a subset of 126 samples with clinically measured viral loads, and with standardized quantification controls (VL 100 -5,000,000 RNA copies/ml). Complete HIV genomes were recovered from 93% (85/91) of samples when viral load was over 1,000 copies per ml. The quantitative nature of the assay implies that variant frequencies estimated with veSEQ-HIV are representative of true variant frequencies in the sample. Detection of minority variants can be exploited for epidemiological analysis of transmission and drug resistance, and we show how the information contained in individual reads of a veSEQ-HIV sample can be used to detect linkage between multiple mutations associated with resistance to antiretroviral therapy. Less than 2% of reads obtained by veSEQ-HIV were identified as in silico contamination events using updates to the phyloscanner software (phyloscanner clean) that we show to be 95% sensitive and 99% specific at 'decontaminating' NGS data. The cost of the assay -approximately 45 USD per sample -compares favourably with existing VL and HIV genotyping tests, and provides the additional value of viral load quantification and inference of drug resistance with a single test. veSEQ-HIV is well suited to large public health efforts and is being applied to all ~9000 samples collected for the HPTN 071-2 (PopART Phylogenetics) study. Figure 1: Information included in the veSEQ-HIV method. The veSEQ-HIV method was developed to provide multiple measurements from a single assay, including viral load, genotype, inference of the transmission events and drug resistance levels.

show abstract

Viral genetic variation accounts for a third of variability in HIV-1 set-point viral load in Europe

Cited by 47 publications

References 55 publications

Dissecting HIV Virulence: Heritability of Setpoint Viral Load, CD4+ T Cell Decline and Per-Parasite Pathogenicity

Dissecting HIV Virulence: Heritability of Setpoint Viral Load, CD4+ T Cell Decline and Per-Parasite Pathogenicity

The phylogenomics of evolving virus virulence

A comprehensive genomics solution for HIV surveillance and clinical monitoring in a global health setting

Contact Info

Product

Resources

About