Innate lymphoid cells are reduced in pregnant HIV positive women and are associated with preterm birth

Abstract

Preterm birth is the leading cause of neonatal and child mortality worldwide. Globally, 1.4 million pregnant women are estimated to be living with HIV/AIDS, the majority of whom live in sub-Saharan Africa. Maternal HIV infection and antiretroviral treatment (ART) have been associated with increased rates of preterm birth, but the underlying mechanisms remain unknown. Acute HIV infection is associated with a rapid depletion of all three subsets of innate lymphoid cells (ILCs), ILC1s, ILC2s and ILC3s, which is not reversed by ART. ILCs have been found at the maternal-fetal interface and we therefore investigated the potential association between maternal HIV infection, peripheral ILC frequencies and preterm birth. In our study of pregnant South African women with accurately dated pregnancies, we show that maternal HIV infection is associated with reduced levels of all three ILC subsets. Preterm birth was also associated with lower levels of all three ILC subsets in early pregnancy. ILC frequencies were lowest in HIV positive women who experienced preterm birth. Moreover, ILC levels were reduced in pregnancies resulting in spontaneous onset of preterm labour and in extreme preterm birth (< 28 weeks gestation). Our findings suggest that reduced ILC frequencies may be a link between maternal HIV infection and preterm birth. In addition, ILC frequencies in early pregnancy may serve as predictive biomarkers for women who are at risk of delivering preterm. Globally, preterm birth (PTB) is the leading cause of neonatal and child mortality, accounting for approximately 18% of deaths in 2016 1. In those infants who survive, PTB is associated with an increased risk of short-and longterm morbidities 2. Preterm birth is a syndrome caused by multiple pathological processes and the underlying mechanisms remain elusive, holding back progress in prediction, prevention and treatment 3. Of the 36.9 million people estimated to be living with HIV/AIDS worldwide 4 , approximately 1.4 million are pregnant women, the majority of whom reside in sub-Saharan Africa 5. A systematic review and meta-analysis conducted by our group revealed that HIV positive expectant mothers not receiving antiretroviral therapy (ART) experienced higher rates of PTB, low birth weight, small-for-gestational-age, and stillbirth than HIV negative women 6. While ART administered during pregnancy is effective at reducing maternal morbidity and mortality as well as mother-to-child HIV transmission, ART does not reverse the effect of HIV on perinatal outcomes and may even exacerbate it, although reports are conflicting 7-14. HIV infection is characterised by a progressive depletion of CD4+ T cells and persistent immune activation 15. In addition, it was recently reported that innate lymphoid cells (ILCs) are depleted during acute HIV infection 16. ILCs are immune effectors which function to provide protective responses against pathogens and tumours and are also involved in lymphoid organogenesis during fetal development 17. They can be divided into three groups, ILC1s...

Maternal HIV infection is associated with distinct systemic cytokine profiles throughout pregnancy in South African women

“…Maternal HIV infection and ART have been associated with an increased risk of adverse perinatal outcomes, including preterm birth and small-for-gestational-age infants 2 , 9 . Peripheral frequencies of a number of immune cells, including CD4 + T cells, γδ T cells, MAIT cells, and innate lymphoid cells (ILCs) have been associated with HIV infection as well as adverse perinatal outcomes, in particular preterm birth 17 – 19 . Therefore, we compared cytokine detection between women who delivered preterm versus those who delivered at term, as well as between women who delivered small-for-gestational-age (SGA) infants versus those who did not.…”

“…Preterm birth (PTB) was defined as birth from 16 +0 to 36 +6 weeks gestation and infants small-for-gestational age (SGA) defined as newborns under the 10th centile of the INTERGROWTH‐21st Newborn Standard birth‐weight‐for‐gestational‐age/sex 63 . Trained study nurses collected peripheral blood samples from WLHIV and HIV-negative pregnant women during the first, second and third trimester, as previously described 17 – 19 . Additional samples were collected at delivery and 6 weeks postnatally from a subset of the WLHIV.…”

Adverse perinatal outcomes associated with protease inhibitor-based antiretroviral therapy in pregnant women living with HIV: A systematic review and meta-analysis

“… 66 Several innate immune cells, including innate lymphoid cells and mucosal associated invariant T cells, are depleted during early HIV infection and fail to recover with ART, and may be associated with increased risk of adverse perinatal outcomes. 67 , 68 ART may promote a pro-inflammatory shift in T-cell function, counteracting the Th1 to Th2 shift required in pregnancy. 69 , 70 The immunological changes in pregnancy are in part driven by placental progesterone.…”

Adverse perinatal outcomes associated with timing of initiation of antiretroviral therapy: Systematic review and meta‐analysis

“…HIV infection is associated with CD4 depletion and chronic immune activation, which may affect the immunological programme of pregnancy [63]. Several innate immune cells, including innate lymphoid cells and mucosal-associated invariant T cells, are depleted during early HIV infection and fail to recover with ART and may be associated with an increased risk of adverse perinatal outcomes [64,65]. One hypothesis proposes an immune-mediated mechanism in which ART causes a type 2 T-helper cell (Th 2 ) to Th 1 shift that counteracts the Th 1 to Th 2 shift seen in pregnancy and ART-naïve HIV infection [66].…”