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.
Highlights
Female children and adults typically generate more efficacious immune responses to vaccines and infections than age-matched males, and suffer greater immunopathology and autoimmune disease
Single stranded RNA viruses such as HIV are sensed by plasmacytoid dendritic cells via expression of TLR7, resulting in higher type I IFN (IFN-I) expression reported in female adults and accelerated activation of antiviral immune responses[4]
To distinguish between the alternative explanations of increased female susceptibility to infection versus increased in utero death in male fetuses following infection, we studied infants born to mothers who themselves became infected during pregnancy
Summary
Female children and adults typically generate more efficacious immune responses to vaccines and infections than age-matched males, and suffer greater immunopathology and autoimmune disease. 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. The stronger IFN-I signalling observed among adult females results in part, from increased expression of TLR7 on a significant subset of innate immune cells. Increased immune activation, which ‘fuels the fire’ of HIV infection[8], increases immunopathology and HIV disease progression in females in chronic infection[4,6] In autoimmune diseases such as SLE where TLR7 dosage is a key pathogenic factor[5], affected females outnumber males by 9:1. We proceed to explore the potential impact of sex-specific innate immune selection of HIV-1 in fetal life on subsequent HIV remission (‘functional cure’)
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