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Population based study indicates viral genetic effect on HIV virulence is small but significant Emma Hodcroft1, Esther Fearnhill2, Andrew Phillips3, David Dunn2, Deenan Pillay4, Jarrod Hadfield5 and Andrew J. Leigh Brown1 on behalf of the UK HIV Drug Resistance Database Previous studies have estimated the genetic effect or heritability (h2) of virulence in HIV at between 5-50%1-5 By analysing the viral phylogeny as a pedigree, h2 can be estimated using wellestablished quantitative genetic methods Of the 3 subtypes analysed (A, B, C), the B subtype produced a significant h2 estimate of 7.7% (CI 4.3-11.0%, p<0.0025) Collapsing poorly-supported nodes in the B-subtype tree did not change the estimate greatly (7.1%; CI 3.6-10.5%, p<0.0025) Sub-sampling the B-subtype tree failed to produce a significant h2 estimate The heritability of virulence in HIV is small but significant, needs a large sample size to be detected, and may be coming from the deeper tree structure data: 55,556 sequences were available from the UK HIV Drug Resistance Database • 11,096 of these had clinical data including viral load from UK CHIC • 539 subtype A, 1,821 subtype C, and 8,483 subtype B sequences and viral loads were analysed • 39 reference sequences from LANL were used as an outgroup Question: How much of the variation in viral load is due to the viral genetic effect? introduction: Pedigree Fig 1 - Pedigree Phylogeny Set-point viral load is an important predictor of virulence in HIV and varies greatly between individuals6 Previous studies have estimated the genetic effect (heritability) of virulence in HIV at between 5-50%1-5 However, these studies have had restricted inclusion and small sample sizes, and many may have been prone to the confounding effects of transmission pair studies Quantitative genetic techniques have been widely used for years to estimate heritability by connecting trait values to the degree of relatedness in pedigrees (Fig 1) By analysing phylogenies constructed from HIV sequences as pedigrees7 (Fig 2) and using these techniques, a large number of samples can be used and potential biases avoided Fig 2 – Phylogeny methods: • Initial viral load was taken as an estimate of setpoint, after excluding potential acute-stage or postART viral load measures • Phylogenies for each of the three subtypes were reconstructed using FastTree8 • Viral load data and phylogenies were linked to form a ‘pedigree’ which was analysed in ASReml9 • Each analysis was compared to a model with no phylogeny to test for significance Emma Hodcroft D-274 [email protected] emmahodcroft.com m.emmahodcroft.com 1University of Edinburgh, UK; 2Medical Research Council Clinical Trials Unit, London, UK; 3Royal Free Hospital, London, UK; 4University College London, UK; 5University of Oxford, UK. summary: contact HIV DRD Steering Committee: tiny.cc/w2xwk Leigh Brown group: www.hivbio.org results: Collapsed Mean Viral Genetic Effect (Conf Interval) 11.9% (-6.8 - 30.6%) No 9.6% (-2.9 - 21.0%) No 7.7% (4.3 - 11.0%) No Significance of Trees (p<0.0025) A C B Dataset Size 539 1,821 8,483 B B (sub-sample) 8,483 2,120 Yes No 7.1% (3.6 - 10.5%) 3.5% (-2.4 - 9.4%) ** B (sub-sample) 4,241 No 5.5% (1.3 - 9.8%) 5/10 were significant† Subtype †If ** only the significant trees are considered: h2 = 7.6% (2.8 - 12.3%) • Only the B-subtype gave a significant h2 estimate, of 7.7% • Collapsing poorly-supported nodes eliminated tip structure but did not affect the estimate • Sub-sampling failed to consistently yield a significant estimate conclusions: • Fig 3 - In the B-subtype tree, poorly-supported branches (bootstrap-equivalents < 0.9) were then collapsed to polytomies and re-analysed • Fig 4 - To investigate the effect of sample size, approximately one-quarter and one-half (N = 2120 & 4241, respectively) of the B-subtype data set was randomly sampled and re-analysed • The heritability of virulence in HIV, at 7.7%, is small, but significant, matching the lower end of previous estimates • The deeper tree structure seems to be the source of the heritability, rather than the tips • A large sample size is needed to detect the heritability of virulence • The sub-samples that were significant were perhaps those that retained the deep tree structure 1. Tang J, et al. AIDS Res Hum Retroviruses 2004;20(1):19-25, references 2. Hollingsworth TD, et al. PLoS Pathog 2010;6:e1000876. 6. Mellors JW, et al. Science 1996;272(5265):1167-70. 3. Alizon S, et al. PLoS Pathog 2010;6(9). 7. Hadfield JD, Nakagawa S. J Evo Biol 2010;23(3):494-508. 4. Hecht FM, et al. AIDS 2010;24(7):941-5. 5. van der Kuyl AC, et al. AIDS 2010;24(10):1607-8. 8. Gilmour AR, et al. www.vsni.co.uk 2009. 9. Price MN, et al. PLoS ONE 2010;5:e9490.