3 years ago

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

Regoes, Rauch, Günthard, Aubert, Kouyos, Böni, Battegay, Bertels, Müller, Yerly, Schmid, Bernasconi, Marzel, Klimkait, Bonhoeffer, Scherrer, Calmy, Cavassini, Fellay, Leventhal, Mitov
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 genetype affects virulence mainly by modulating the per-parasite pathogenicity, while the indirect effect via the set-point viral load is minor.

Publisher URL: http://doi.org/10.1093/molbev/msx246

DOI: 10.1093/molbev/msx246

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