The research, published in Proceedings of the National Academy of Sciences (PNAS), shows that ART is not only transforming outcomes for people living with HIV, but is also interrupting a process of natural selection on immune system genes (specifically variants of HLA-B) that could otherwise have reshaped human genetics over just a few decades.
Chimpanzees, the closest living relatives of humans, are believed to have experienced selective sweeps over two million years ago, that biased their immune gene repertoires towards variants that conferred protection against the progression of disease caused by viruses similar to HIV. This study highlights that the unchecked spread of HIV could have had a similar impact on humans, were it not for access to effective antiviral drug combination therapies.
Drawing on longitudinal data from antenatal cohorts in KwaZulu-Natal, South Africa - one of the regions most heavily affected by HIV - the team compared outcomes in the pre-ART era (1998–2005) with those in the modern treatment era (2015–2025).
The study found that, prior to ART rollout, genetic variants associated with poorer HIV control increased the likelihood of both rapid disease progression to AIDS and vertical HIV transmission to children. Conversely, protective variants were linked to slower disease progression and reduced vertical transmission.
Using these data, the researchers modelled how HIV could have influenced gene frequencies in the KwaZulu-Natal population over time. In a scenario without ART, they estimate that, between 1990 and 2035, the frequency of protective HLA-B variants would have doubled, while disease-susceptible variants would have declined by approximately 38%.
However, the introduction and scale-up of ART has essentially halted this evolutionary process by improving survival regardless of genotype, and by eliminating the link between maternal genetics and mother-to-child transmission of HIV in treated individuals.
Professor Philip Goulder, senior author from the Department of Paediatrics at the University of Oxford, said: “This study provides rare evidence of the scale of population genetic change that an infectious disease can drive over a relatively short timescale. What is remarkable is that modern medicine, through the rollout of antiretroviral therapy, has effectively interrupted this process of natural selection.”
He added: “By suppressing HIV and preventing transmission, ART removes the differential survival and reproductive effects that would otherwise favour certain genetic variants. In doing so, it not only saves lives but also alters the evolutionary trajectory of the human population.”
The findings also address a long-standing hypothesis in evolutionary biology, that infectious diseases maintain diversity in immune system genes, by modelling how rapidly the frequencies of such genes could change in human populations.
Dr Bridget Penman, co-senior author from the Department of Biology at the University of Oxford, said: “HLA genes, which we study here, are some of the most diverse in the human genome. Our best explanation for this diversity is that they are subject to natural selection from co-evolving, rapidly changing, pathogens. However, most models of this process are conceptual. Here we have simulated changes in the frequencies of known HLA variants, in a specific population, driven by HIV.”
She continued: “HIV is the only pathogen for which we have enough data to predict how rapidly a lethal infectious disease can impact HLA frequencies. Estimating the size and speed of HIV-driven population genetic change that has been averted by ART demonstrates the profound public health success of ART, and at the same time gives us insight into a fundamental evolutionary process underpinning human immunogenetics.”
The study also highlights the broader implications of treatment access. While ART has largely neutralised HLA-driven differences in HIV outcomes, the authors note that incomplete access or adherence means that some degree of selective pressure may still persist.
Overall, the research underscores both the biological impact of the HIV pandemic and the transformative role of global treatment programmes, not only in controlling disease, but in shaping the future of human genetic diversity.