Sex-specific innate immune selection of HIV-1 in utero is associated with increased female susceptibility to infection
Emily Adland, Jane Millar, Nomonde Bengu, Maximilian Muenchhoff, Rowena Fillis, Kenneth Sprenger, Vuyokasi Ntlantsana, Julia Roider, Vinícius Vieira, Katya Govender, John Adamson, Nelisiwe Nxele, Christina Ochsenbauer, John C. Kappes, Luisa Mori, Jeroen van Lobenstein, Yeney Graza, Kogielambal Chinniah, Constant Kapongo, Roopesh Bhoola, Malini Krishna, Philippa C. Matthews, Ruth Penya Poderos, Marta Colomer-Lluch, María C. Puertas, Júlia G. Prado, Neil McKerrow, Moherndran Archary, Thumbi Ndung’u, Andreas Groll, Pieter Jooste, Javier Martínez‐Picado, Marcus Altfeld, Philip Goulder
Abstract
Female children and adults typically generate more efficacious immune responses to vaccines and infections than age-matched males, but also suffer greater immunopathology and autoimmune disease. We here describe, in a cohort of > 170 in utero HIV-infected infants from KwaZulu-Natal, South Africa, fetal immune sex differences resulting in a 1.5-2-fold increased female susceptibility to intrauterine HIV infection. Viruses transmitted to females have lower replicative capacity (p = 0.0005) and are more type I interferon-resistant (p = 0.007) than those transmitted to males. Cord blood cells from females of HIV-uninfected sex-discordant twins are more activated (p = 0.01) and more susceptible to HIV infection in vitro (p = 0.03). Sex differences in outcome include superior maintenance of aviraemia among males (p = 0.007) that is not explained by differential antiretroviral therapy adherence. These data demonstrate sex-specific innate immune selection of HIV associated with increased female susceptibility to in utero infection and enhanced functional cure potential among infected males.