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, Vinicius Vieira, Katya Govender, John Adamson, Nelisiwe Nxele, Christina Ochsenbauer, John Kappes, Luisa Mori, Jeroen Lobenstein, Yeney Graza, Kogielambal Chinniah, Constant Kapongo, Roopesh Bhoola, Malini Krishna, Philippa C. Matthews, Ruth Penya Poderos, Marta Colomer Lluch, Maria C. Puertas, Julia G. Prado, Neil McKerrow, Moherndran Archary, Thumbi Ndung’u, Andreas Groll, Pieter Jooste, Javier Martinez-Picado, Marcus Altfeld and Philip Goulder ()
Additional contact information
Emily Adland: Department of Paediatrics, University of Oxford
Jane Millar: Department of Paediatrics, University of Oxford
Nomonde Bengu: Umkhuseli Innovation and Research Management
Maximilian Muenchhoff: Max von Pettenkofer Institute, Virology, National Reference Center for Retroviruses, Faculty of Medicine, LMU München
Rowena Fillis: Umkhuseli Innovation and Research Management
Kenneth Sprenger: Umkhuseli Innovation and Research Management
Vuyokasi Ntlantsana: Department of Medicine, University of KwaZulu-Natal
Julia Roider: German Center for Infection Research (DZIF), Partner site Munich
Vinicius Vieira: Department of Paediatrics, University of Oxford
Katya Govender: Africa Health Research Institute
John Adamson: Africa Health Research Institute
Nelisiwe Nxele: HIV Pathogenesis Programme, The Doris Duke Medical Research Institute, University of KwaZulu-Natal
Christina Ochsenbauer: Department of Medicine, University of Alabama at Birmingham
John Kappes: Department of Medicine, University of Alabama at Birmingham
Luisa Mori: Department of Paediatrics, University of Oxford
Jeroen Lobenstein: Stanger Hospital, KwaDukuza
Yeney Graza: KwaZulu-Natal Department of Health
Kogielambal Chinniah: Mahatma Gandhi Memorial Hospital
Constant Kapongo: Queen Nandi Regional Hospital, Empangeni
Roopesh Bhoola: Edendale Hospital, Pietermartizburg
Malini Krishna: Edendale Hospital, Pietermartizburg
Philippa C. Matthews: Nuffield Department of Medicine, University of Oxford
Ruth Penya Poderos: IrsiCaixa AIDS Research Institute, Germans Trias i Pujol Research Institute (IGTP)
Marta Colomer Lluch: IrsiCaixa AIDS Research Institute, Germans Trias i Pujol Research Institute (IGTP)
Maria C. Puertas: IrsiCaixa AIDS Research Institute, Germans Trias i Pujol Research Institute (IGTP)
Julia G. Prado: IrsiCaixa AIDS Research Institute, Germans Trias i Pujol Research Institute (IGTP)
Neil McKerrow: KwaZulu-Natal Department of Health
Moherndran Archary: Department of Paediatrics, University of KwaZulu-Natal
Thumbi Ndung’u: HIV Pathogenesis Programme, The Doris Duke Medical Research Institute, University of KwaZulu-Natal
Andreas Groll: TU Dortmund University, Faculty of Statistics
Pieter Jooste: Department of Paediatrics, Kimberley Hospital
Javier Martinez-Picado: IrsiCaixa AIDS Research Institute, Germans Trias i Pujol Research Institute (IGTP)
Marcus Altfeld: Virus Immunology Unit, Heinrich-Pette-Institut
Philip Goulder: Department of Paediatrics, University of Oxford

Nature Communications, 2020, vol. 11, issue 1, 1-9

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-15632-y

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