Abstract
Transmission bottlenecks introduce selection pressures on HIV-1 that vary with the mode of transmission. Recent studies on small cohorts have suggested that stronger selection pressures lead to fitter transmitted/founder (T/F) strains. Manifestations of this selection bias at the population level have remained elusive. Here, we analysed early CD4 cell count measurements reported from ∼340,000 infected heterosexual individuals (HET) and men-who-have-sex-with-men (MSM), across geographies, ethnicities and calendar years. The reduction in CD4 counts early in infection is reflective of the virulence of T/F strains. MSM and HET use predominant modes of transmission, namely, anal and penile-vaginal, with among the largest differences in the selection pressures at transmission across modes. Further, in most geographies, the groups show little inter-mixing, allowing for the differential selection bias to be sustained and amplified. We found that the early reduction in CD4 counts was consistently greater in HET than MSM (P<0.05). To account for inherent variations in baseline CD4 counts, we constructed a metric to quantify the extent of progression to AIDS as the ratio of the reduction in measured CD4 counts from baseline and the reduction associated with AIDS. We found that this progression corresponding to the early CD4 measurements was ∼68% for MSM and ∼87% for HET on average (P<10-4; Cohen's d, ds = 0.36), reflecting the more severe disease caused by T/F strains in HET than MSM at the population level. Interestingly, the set-point viral load was not different between the groups (ds<0.12), suggesting that MSM were more tolerant and not more resistant to their T/F strains than HET. This difference remained when we controlled for confounding factors using multivariable regression. We concluded that the different selection pressures at transmission have resulted in more virulent T/F strains in HET than MSM. These findings have implications for our understanding of HIV-1 pathogenesis, evolution, and epidemiology.
Highlights
The bottlenecks in HIV-1 transmission result in a ‘selection bias’ favoring fitter transmitted/ founder (T/F) viruses over less fit ones [1, 2]
CD4 count measurements made early in infection tend to be close to the value to which the counts settle after the initial dynamics
These early CD4 counts are expected to be minimally affected by host-specific adaptive mutations [1] and, reflective of the effects of the T/F strains
Summary
The bottlenecks in HIV-1 transmission result in a ‘selection bias’ favoring fitter transmitted/ founder (T/F) viruses over less fit ones [1, 2]. From 137 heterosexual (HET) donor-recipient pairs, T/F viruses were found to carry higher than average frequencies of amino acids associated with high in vivo fitness, in terms of protein stability, immune escape and compensation [1]. Analysis of T/F genomes from 131 subjects revealed that the T/F genomes were under greater positive selection in heterosexual individuals (HET), in whom the penile-vaginal mode predominates [8], than homosexual men, or men-who-have-sex-with-men (MSM), who transmit predominantly through anal intercourse [3]. Among HET, men had T/F viruses with higher predicted fitness in vivo than women [1], consistent with the asymmetry of the bottlenecks between insertive and receptive penile-vaginal intercourse [7]
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