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The disparity between the male and female immune response is clear in HIV infection: females typically achieve viral loads 0.5 log10 lower than males and are 5-fold more likely to achieve elite control. However, females are more likely to lose viral control once achieved and progress to AIDS faster than males for matched viral loads. The more aggressive female immune response seen in HIV, also seen of other infections and vaccine responses, may be explained by the higher production of type 1 interferon (IFN-I) by female immune cells. The upstream receptor responsible for recognising virus infection and this initiating IFN-I production, TLR7, is encoded on the X-chromosome and escapes X-chromosome inactivation in a proportion of cells to be doubly expressed on >40% of immune cells.

To test the hypothesis that a stronger IFN-I innate immune response might increase the susceptibility of females to in-utero HIV infection, we are characterising the IFN-I-sensitivity of the virus transmitted from mother-to-child in the Babycure study. This work led by Emily Adland (Adland et al., Nat Comms 2020) has shown that IFN-I-resistant viruses tend to be transmitted to female foetuses, while IFN-I-sensitive viruses are preferentially transmitted to male foetuses. The female susceptibility to in-utero HIV infection is maximal when the mother herself becomes infected during pregnancy, prompting the hypothesis that IFN-I-resistant viruses are preferentially transmitted in male-to-female adult HIV transmission, and are then outgrown by IFN-I-sensitive viruses following transmission. We are addressing this with adult transmission pairs from the ZEHRP cohort, working in collaboration with Eric Hunter at Emory University and aim to ascertain both IFN-I-sensitivity and viral replicative capacity (VRC) of transmitted viruses. VRC is indeed lower in in-utero infected females than males, consistent with the overall notion that female foetuses are more susceptible to intrauterine mother-to-child transmission.