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

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.

Fig 1. Marker and risk groups for assessing selection bias at transmission.

(A) Schematic of typical CD4 count changes post HIV-1 infection (blue), before (dashed) and after (solid) diagnosis/seroconversion. The reduction at diagnosis/seroconversion relative to uninfected individuals (orange) and that associated with AIDS (grey dashed line) yields R_T/F, the reduction attributable to the T/F virus. (B-C) HIV-1 subtype prevalence in MSM and HET populations. Prevalence of (B) subtype B in different regions in Europe and Canada and (C) all the subtypes in China. (CV denotes Communidad Valenciana.) The sample sizes (n) along with the time periods of the surveys are indicated. P values are listed where available from the original sources (see S1 and S2 Tables).

Fig 2. Early CD4 T cell counts in MSM and HET.

Early mean CD4 cell counts in untreated infected adult HET and MSM from different geographical regions and calendar years (see Methods, Table 1 and S3–S5 Tables). The grey region indicates counts in uninfected, healthy individuals. The sample sizes (n) are shown. SCs are seroconverters. ****, ***, ** and * indicate P<10⁻⁴, P<10⁻³, P<10⁻² and P<0.05, respectively.

Fig 3. The relative reduction in early CD4 counts (R_T/F) in MSM and HET.

R_T/F in untreated infected adult HET and MSM from different geographical regions and calendar years (see Methods, Table 1 and S3–S6 Tables for details). The sample sizes (n) are indicated. SCs indicate seroconverters. ****, ***, ** and * indicate P<10⁻⁴, P<10⁻³, P<10⁻² and P<0.05, respectively.

Fig 4. Association with transmission clusters.

(A) The fraction of HET and MSM (or bisexuals in one case) associated with transmission clusters and (B) the size and composition of the largest clusters in different geographical regions. The sample sizes (n) along with the time periods of the surveys are indicated. P values and the minimum sizes of the clusters (blue text) where available from the original sources are listed (see S8 Table).