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

Frederic Bertels, Alex Marzel, Gabriel Leventhal, Venelin Mitov, Jacques Fellay, Huldrych F Günthard, Jürg Böni, Sabine Yerly, Thomas Klimkait, Vincent Aubert, Manuel Battegay, Andri Rauch, Matthias Cavassini, Alexandra Calmy, Enos Bernasconi, Patrick Schmid, Alexandra U Scherrer, Viktor Müller, Sebastian Bonhoeffer, Roger Kouyos, Roland R Regoes & Swiss HIV Cohort Study

abstract 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 CD4+ 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 CD4+ 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 CD4+ T-cell declines and per-parasite 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 CD4+ 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 CD4+ 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.
   
citation Bertels F, Marzel A, Leventhal G, Mitov V, Fellay J, Günthard H F, Böni J, Yerly S, Klimkait T, Aubert V, Battegay M, Rauch A, Cavassini M, Calmy A, Bernasconi E, Schmid P, Scherrer A U, Müller V, Bonhoeffer S, Kouyos R, Regoes R R, Swiss HIV Cohort Study . Dissecting HIV Virulence: Heritability of Setpoint Viral Load, CD4+ T-Cell Decline, and Per-Parasite Pathogenicity. Mol Biol Evol 2018; 35:27-37.
   
type journal paper/review (English)
date of publishing 01-1-2018
journal title Mol Biol Evol (35/1)
ISSN electronic 1537-1719
pages 27-37
PubMed 29029206
DOI 10.1093/molbev/msx246