Transmitted HIV-1 is more virulent in heterosexual individuals than men-who-have-sex-with-men

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. Author summary HIV-1 encounters a key bottleneck at the time of its transmission from one individual to another. This transmission bottleneck can differ between modes of transmission. The stronger this bottleneck is, the more fit the virus has to be to be successfully transmitted. Accordingly, the transmitted/founder (T/F) strains of HIV-1 may have different fitness in risk groups that use different modes of transmission. While studies on small cohorts do support this notion, observations of the manifestations of this differential selection bias at the population level have been lacking. Here, we examined reported early CD4 count measurements from ∼340,000 HET and MSM, across geographies, ethnicities, and calendar years. Early CD4 counts are a measure of the severity of the infection due to T/F strains. HET and MSM transmit predominantly via penile-vaginal and anal modes, respectively, and do not inter-mix significantly. Remarkably, we found that HET consistently had lower early CD4 counts than MSM. This difference could not be attributed to potential confounding factors, such as set-point viral load. The difference thus provided evidence that T/F strains had evolved to be more virulent in HET than MSM at the population level. Intervention strategies may benefit from accounting for this difference between risk groups.