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.

Figure 1

ILC1, ILC2 and ILC3 cells throughout pregnancy. (a) Gating strategy identifying ILC1, ILC2 and ILC3 cells among live, lineage negative (Lin-) CD45+ lymphocytes. (b) ILC1, (c) ILC2 and (d) ILC3 cell frequencies of all women studied (i.e. both HIV+ and HIV− women) during the first (T1), second (T2) and third (T3) trimester. (e) ILC1, (f) ILC2 and (g) ILC3 cell frequencies of HIV positive (HIV+) women during the first, second and third trimester and at delivery and six weeks postnatal. Data bars at median.

Figure 2

ILC1, ILC2 and ILC3 cells of HIV positive and HIV negative women throughout pregnancy. (a) ILC1, (b) ILC2 and (c) ILC3 cell frequencies of HIV positive (HIV+) and HIV negative (HIV−) women during the first (T1), second (T2) and third (T3) trimester. Data bars at median.

Figure 3

ILC1, ILC2 and ILC3 cells of HIV positive and/or HIV negative women with preterm or term births. (a) ILC1, (b) ILC2 and (c) ILC3 cell frequencies of women who delivered preterm (PTB) compared to those who delivered at term. (d–f) First (T1), (g–i) second (T2) and (j–l) third (T3) trimester ILC1, ILC2 and ILC3 frequencies, respectively, of HIV positive (HIV+) and HIV negative (HIV−) women who delivered preterm (PTB) or at term. Data bars at median.

Figure 4

ILC1, ILC2 and ILC3 cells of HIV positive and/or HIV negative women with different severities of preterm birth or term birth. (a) ILC1, (b) ILC2 and (c) ILC3 cell frequencies of women who had moderate preterm (m.PTB), very preterm (v.PTB), or extreme preterm (e.PTB) births compared to those who delivered at term. (d–f) First (T1), (g–i) second (T2) and (j–l) third (T3) trimester ILC1, ILC2 and ILC3 frequencies, respectively, of HIV positive (HIV+) and HIV negative (HIV−) women who had term, moderate preterm, very preterm, or extreme preterm births. Data bars at median.

Figure 5

ILC1, ILC2 and ILC3 cells of HIV positive and/or HIV negative women with spontaneous onset of labour and preterm or term births. (a) ILC1, (b) ILC2 and (c) ILC3 cell frequencies of women with spontaneous onset of labour who delivered preterm (PT) compared to those who delivered at term (T). (d–f) First (T1), (g–i) second (T2) and (j–l) third (T3) trimester ILC1, ILC2 and ILC3 frequencies, respectively, of HIV positive (HIV+) and HIV negative (HIV−) women with spontaneous onset of labour who delivered preterm (PT) or at term (T). Data bars at median.