Inflammation and cytomegalovirus viremia during pregnancy drive sex-differentiated differences in mortality and immune development in HIV-exposed infants

Ceri Evans (), Kuda Mutasa, Sandra Rukobo, Margaret Govha, Patience Mushayanembwa, Bernard Chasekwa, Florence D. Majo, Naume V. Tavengwa, Jonathan Broad, Christie Noble, Ethan K. Gough, Paul Kelly, Claire D. Bourke, Jean H. Humphrey, Robert Ntozini and Andrew J. Prendergast
Additional contact information
Ceri Evans: Zvitambo Institute for Maternal and Child Health Research
Kuda Mutasa: Zvitambo Institute for Maternal and Child Health Research
Sandra Rukobo: Zvitambo Institute for Maternal and Child Health Research
Margaret Govha: Zvitambo Institute for Maternal and Child Health Research
Patience Mushayanembwa: Zvitambo Institute for Maternal and Child Health Research
Bernard Chasekwa: Zvitambo Institute for Maternal and Child Health Research
Florence D. Majo: Zvitambo Institute for Maternal and Child Health Research
Naume V. Tavengwa: Zvitambo Institute for Maternal and Child Health Research
Jonathan Broad: Queen Mary University of London
Christie Noble: Queen Mary University of London
Ethan K. Gough: Johns Hopkins Bloomberg School of Public Health
Paul Kelly: Queen Mary University of London
Claire D. Bourke: Zvitambo Institute for Maternal and Child Health Research
Jean H. Humphrey: Zvitambo Institute for Maternal and Child Health Research
Robert Ntozini: Zvitambo Institute for Maternal and Child Health Research
Andrew J. Prendergast: Zvitambo Institute for Maternal and Child Health Research

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: Abstract Children who are HIV-exposed but uninfected have increased infectious mortality compared to HIV-unexposed children, raising the possibility of immune abnormalities following exposure to maternal viraemia, immune dysfunction, and co-infections during pregnancy. In a secondary analysis of the SHINE trial in rural Zimbabwe we explored biological pathways underlying infant mortality, and maternal factors shaping immune development in HIV-exposed uninfected infants. Maternal inflammation and cytomegalovirus viraemia were independently associated with infant deaths: mortality doubled for each log10 rise in maternal C-reactive protein (adjusted hazard ratio (aHR) 2.09; 95% CI 1.33–3.27), and increased 1.6-fold for each log10 rise in maternal cytomegalovirus viral load (aHR 1.62; 95% CI 1.11–2.36). In girls, mortality was more strongly associated with maternal C-reactive protein than cytomegalovirus; in boys, mortality was more strongly associated with cytomegalovirus than C-reactive protein. At age one month, HIV-exposed uninfected infants had a distinct immune milieu, characterised by raised soluble CD14 and an altered CD8 + T-cell compartment. Alterations in immunophenotype and systemic inflammation were generally greater in boys than girls. Collectively, these findings show how the pregnancy immune environment in women with HIV underlies mortality and immune development in their offspring in a sex-differentiated manner, and highlights potential new intervention strategies to transform outcomes of HIV-exposed children. ClinicalTrials.gov/NCT01824940.

Date: 2024
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DOI: 10.1038/s41467-023-44166-2

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