Background
HLA is the most polymorphic region in the human genome, as the differential HLA-dependent impact of certain infections, inflammatory conditions, autoimmune diseases and cancers drive its evolution. However, clear examples of infection-driven evolution are rare. Here, we investigated antenatal cohorts in KwaZulu-Natal (KZN), South Africa, the region most severely affected by the global HIV pandemic, to evaluate the influence of HIV-1 infection on population-level HLA-I frequencies, and the impact of antiretroviral therapy (ART) in reversing this process.
Methods
In a historical cohort of antenatal mothers living with HIV (LWH) in KZN, South Africa, in the pre-ART era between 2002-2005, we compared frequencies of ‘protective’ HLA-B alleles (HLA-B*57/B*58:01/B*81:01) associated with low viral setpoints and slow disease progression, and ‘disease-susceptible’ HLA-B alleles (HLA-B*18/B*45:01/B*58:02) associated with high viral setpoints and rapid disease progression, among non-transmitting mothers (n=559) and transmitting mother-child pairs (n=112) . Next, we compared these HLA-B frequencies to those in a contemporary antenatal cohort of mothers LWH in KZN enrolled in the ART era between 2015-2023 (n=233). Lastly, we constructed an epidemiological model from 1990 to 2035 simulating the HIV-1 epidemic in KZN to describe observed HLA-B frequencies, and a counterfactual scenario where ART was never rolled out.
Results
In the pre-ART era, ‘disease-susceptible’ HLA-B alleles were significantly associated with an increased risk of vertical transmission (OR 2, p=0.018), whilst ‘protective’ HLA-B alleles lead to a decreased risk of vertical transmission (OR 0.51, p=0.004). Disease-susceptible HLA-B alleles were significantly enriched in transmitting mother-child pairs (p=0.006) and ‘protective’ HLA-B alleles enriched in non-transmitting mothers (p=ns). In the ART era, this process has been reversed. The model that was constructed, simulating the differential impact of HLA-B alleles on disease progression and vertical transmission, indicated that, in the absence of ART, the HIV epidemic would have reduced KZN population frequencies of ‘disease-susceptible’ HLA-B allele by 50% and increased those of ‘protective’ HLA-B alleles two-fold by 2035.
Conclusions
We demonstrate that, in the pre-ART era, the HIV-1 epidemic drives reduction in the population-level frequency of HLA-I alleles mediating rapid HIV disease progression. This process of negative natural selection has been reversed by the impact of ART.
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