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

['Ananthu James', 'Department Of Chemical Engineering', 'Indian Institute Of Science', 'Bengaluru', 'Narendra M. Dixit', 'Centre For Biosystems Science', 'Engineering']

Date: 2022-05

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, d s = 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 (d s <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.

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.

An important question that follows is whether the differential selection bias across modes of transmission is manifested at the wider population level, extending beyond the restricted cohorts examined in the trials above. Such differential bias could contribute to variations in disease progression and treatment outcomes and underlie the diverse trajectories of the HIV-1 pandemic across infected groups in which different modes of transmission predominate. To answer this question, a marker of the manifestation of the fitness of the T/F viruses that is readily measured across large populations is necessary. Furthermore, infected groups must be identified in which the predominant modes of transmission have substantial differences in the associated bottlenecks, so that the implications of the selection bias are detectable with statistical significance. Here, we identified CD4 T cell counts measured early in infection as a suitable marker meeting the above criteria and MSM and HET as the relevant risk groups. We collated early CD4 count measurements in these groups across large populations and in different geographies and calendar years and analyzed them to deduce the impact of the differential selection bias across modes of transmission at the population level.

The selection bias varies with the mode of transmission [ 3 ]. The stronger the bottlenecks, the fitter the corresponding T/F viruses are likely to be [ 1 , 2 ]. Anal intercourse is over 10-fold more permissive on average than penile-vaginal intercourse [ 7 ]. 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 ].

The bottlenecks in HIV-1 transmission result in a ‘selection bias’ favoring fitter transmitted/founder (T/F) viruses over less fit ones [ 1 , 2 ]. Several recent studies have presented evidence of genetic, phenotypic, and clinical manifestations of the selection bias in small cohorts [ 1 , 3 – 6 ]. The evidence is based on different attributes of fitness, each contributing to the establishment of infection and progressive disease. For instance, 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 ]. Similarly, from 127 discordant couples, higher viral replication capacity (vRC) early in infection was associated with faster decline of CD4 T cell counts [ 4 ].

Results

Relative reduction in CD4 counts early in infection While the evidence from absolute CD4 count comparisons was thus strong, differences in CD4 counts in healthy (uninfected) individuals across sex, ethnicity and geographical regions could render absolute CD4 counts only an approximate measure of the virulence of the T/F strains. Two individuals may have similar early CD4 counts but may still have been infected by T/F strains of different fitness if their pre-infection CD4 counts were different, with the individual with the higher pre-infection count infected by the more virulent T/F strain. To overcome this limitation, we constructed a metric to quantify the relative reduction in the CD4 cell count, R, corresponding to the absolute CD4 count, T, as , where T healthy was the count pre-infection and T AIDS = 200 cells/μL the count defining AIDS. R thus represented the reduction in CD4 counts, ΔCD4, relative to the reduction signifying AIDS, ΔCD4 AIDS . Accordingly, R was 0% when T = T healthy and 100% when T = T AIDS and decreased linearly with T between these extremes. R was thus a more reliable indicator of disease severity than absolute CD4 counts. To use this metric, we collated measurements of T healthy specific to the respective geographies, ethnicities, and sexes [32, 35–39] (S6 Table). Using the latter data, we estimated R corresponding to the early cell count measurements above, which we denoted as R T/F , indicative of the relative reduction in CD4 count due to the T/F virus (Fig 3 and Table 1). The higher the R T/F , the more virulent would be the T/F strain. (Note that R T/F is a static measure and is not indicative of the ‘speed’ of disease progression; subsequent cell count decline can be faster despite higher early CD4 counts in MSM than HET [29, 40].) PPT PowerPoint slide

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TIFF original image Download: 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. https://doi.org/10.1371/journal.ppat.1010319.g003 We found that in EU/EAA, during 2010–18, R T/F was 86.2% in HET and 66.2% in MSM (P<10−4; d s = 0.54). During 2002–07, these numbers were 88.8% and 67.8% (P<10−4; d s = 0.57), respectively. The corresponding numbers were 96.0% and 78.2% in the UK (P<10−4; d s = 0.45), and 86.7% and 68.0% in China (P<10−4; d s = 0.38). In the US, the difference was smaller but still substantial, with R T/F of 85.8% in HET and 73.7% in MSM (P<10−4; d s = 0.35). At seroconversion, these numbers were 64.7% and 51.0%, respectively (P<10−4; d s = 0.29). For the seroconverters from the CASCADE study, the trend was consistent, with R T/F of 47.1% in HET and 40.7% in MSM (P<10−3; d s = 0.12). In some studies, data was available separately for HET men and women, allowing a comparison between HET men and MSM, thus eliminating potential confounding effects of sex (Table 1). In EU/EEA, during 2010–18, R T/F in HET men was 90%, much higher than the 82.9% in HET women, indicating that the difference between HET and MSM was amplified upon eliminating the effect of sex. We recall that R T/F was 66.2% in MSM during the same period, significantly smaller than HET men (P<10−4; d s = 0.63) and HET women (P<10−4; d s = 0.20). Among the seroconverters in Europe and Australia, in those aged below 40 years, R T/F in HET men was 46.4%, higher than the 40% in MSM (P = 0.01; d s = 0.12). The difference was similar in those aged above 40 years; R T/F was 52.4% in HET men and 46.2% in MSM (P = 0.073; d s = 0.16). Thus, in these comparisons too, where the effects of sex, age, and diagnosis delay were eliminated, HET had a consistently higher R T/F than MSM. Overall, thus, R T/F comparisons showed more significant differences between MSM and HET than absolute CD4 count comparisons (see Figs 2 and 3). Further, R T/F allowed comparison across the different datasets. Thus, while the HET all had R T/F >85% at diagnosis, the MSM displayed a range from ∼65% to a little under 80%. This was comprehensive evidence of the greater virulence of the T/F virus in HET than MSM.

Set-point viral load To understand this finding further, we recognized that virulence can have pathogen load-dependent and -independent components [10, 11]. If pathogen load-dependent components were predominant, HET would have higher pathogen loads on average than MSM, which would then explain the higher R T/F . The set-point viral load (SPVL) is established within weeks of infection and stays nearly constant for years [9], and is recognized as a good measure of the pathogen load in HIV-1 infection [10, 11]. A subset of the above studies reported SPVL along with early CD4 counts. We found in the latter studies that the mean SPVL was similar in MSM and HET, with the effect sizes negligible and no consistent trend towards higher SPVL in HET (Table 2). For instance, the mean SPVL was 4.4 log 10 copies/mL for both MSM and HET in the CASCADE study from 2006–2009 (P = 0.5; d s = 0.00). SPVL thus could not explain the differences in R T/F between MSM and HET. It is possible that viral loads in primary infection, before the establishment of SPVL, could be higher in HET than MSM. Measurements of viral load in primary infection are rare. A recent study did measure viral loads in primary infection in MSM and HET in a small sample (n ∼ 20 each) and found no difference between the groups (P = 0.34) [3]. While this finding needs to be established more widely, it suggests that the differences in R T/F in the two groups are unlikely to have originated from differences in the pathogen load. PPT PowerPoint slide

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TIFF original image Download: Table 2. Set-point viral load and relative per parasite pathogenicity of T/F strains in HET and MSM. SPVL*, early CD4 cell counts, the corresponding R T/F in infected adults at seroconversion (from the CASCADE study [41]) or diagnosis (from the Europe study [19]). For the CASCADE data, the mean and SD were calculated from the median and 95% CIs (see Methods) obtained by digitizing using WebPlotDigitizer. The 95% CIs provided here are following the normal approximation. Information for the European study is in Table 1. https://doi.org/10.1371/journal.ppat.1010319.t002

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[1] Url: https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1010319

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