A ground-breaking, world-first international study published in the prestigious peer-reviewed journal Nature Medicine shows that male infants are more likely to achieve HIV cure/remission than female infants.

The study included scientists from Africa Health Research Institute (AHRI), the Universities of KwaZulu-Natal (UKZN) and Oxford, as well as the Ragon Institute of Mass General, and Massachusetts Institute of Technology Harvard, USA. The observational study took place between 2015-2023 and included 284 mother-child pairs living with HIV (LWH) in KwaZulu-Natal, South Africa – the epicentre of HIV prevalence globally.

The study assessed 284 children from KwaZulu-Natal in whom anti-HIV therapy was initiated at birth following in utero HIV transmission. Sixty percent of the cohort were female. Vertical transmission to male foetuses was 50% less common than to females. Affected males had lower levels of the virus in the blood and to date, in this study, four male infants have been identified who have achieved HIV cure/remission (i.e., maintained undetectable levels of HIV in the blood even without therapy).

The reason for these different outcomes between males and females is two-fold: firstly, studies have indicated that female foetuses, like their adult counterparts, typically make stronger immune responses than males. However, an overly active immune response can increase susceptibility to infections such as HIV. Secondly, the female foetus shares with her mother the same type of innate immune response. Therefore, the female foetus is particularly susceptible to the viruses that have evaded maternal immunity. The male foetus, by contrast, is relatively resistant to these viruses in the mother. The consequence is that, even when transmission does arise in male foetuses, infection may not be sustained.

An interesting observation of the study indicated that in five sex-discordant twin sets in the cohort, HIV was only acquired in the female twin. This is further evidence that in utero transmission of HIV is higher in female foetuses due to the higher levels of immune activation both antenatally and postnatally, making female foetuses more susceptible to infection in the first two years of life.

“This is a breakthrough result in South Africa, where almost eight million people are living with HIV. This will transform the way that people here view HIV and will provide much-needed hope for the future,” said Dr Nomonde Bengu, a clinician and lead researcher on the study at Queen Nandi Regional Hospital in KwaZulu-Natal.

“These results are exciting because, first of all, HIV cure/remission is very rare and this study highlights the fact that it nonetheless is achievable. Furthermore, we have identified some of the key mechanisms by which HIV cure/remission can be achieved, and this is relevant to cure strategies not only aimed at children but those targeting all 39 million people living with HIV,” said Professor Philip Goulder, an AHRI faculty member and professor of immunology at the Department of Paediatrics at Oxford.

“While this study is highly encouraging in showing that cure/remission can happen in a small subset of children, especially in male children, following very early initiation of therapy, it is clear that other interventions are also necessary, such as broadly neutralising antibody therapy and T-cell vaccines, in order to make the size of impact that is urgently needed in the cure field. Our team is excited to be part of taking this field forward,” said Dr Gabriela Cromhout, a lead researcher on the study from UKZN.

The study, titled ‘Sustained aviraemia despite anti-retroviral therapy non-adherence in male children following in utero HIV transmission’, was supported by funding from the Wellcome Trust, the National Institutes of Health and the PENTA Foundation.

Top photo: Prof Philip Goulder, AHRI faculty member and lead author on the paper.