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

Abstract

Maternal HIV infection is associated with adverse pregnancy outcomes, but the mechanisms remain unknown. The course of pregnancy is regulated by immunological processes and HIV infection and antiretroviral therapy (ART) impact key immune mechanisms, which may disrupt the immune programme of pregnancy. We evaluated a broad range of systemic cytokines at each trimester of pregnancy in 56 women living with HIV (WLHIV) and 68 HIV-negative women, who were enrolled in a prospective pregnancy cohort study in Soweto, South Africa. The pro-inflammatory cytokine IP-10 was detected in each trimester in all WLHIV, which was significantly more than in HIV-negative women. The anti-viral cytokine IFNλ1 was detected more frequently in WLHIV, whereas IFNβ and IFNλ2/3 were detected more frequently in HIV-negative women. Th1 cytokines IL-12 and IL-12p70, Th2 cytokine IL-5, and Th17 cytokine IL-17A were detected more frequently in WLHIV throughout pregnancy. Il-6, IL-9, and IL-10 were more commonly detected in WLHIV in the first trimester. Trends of increased detection of Th1 (IL-2, IL-12p70), Th2 (IL-4, Il-5, Il-13) and Th17 (IL-17A, Il-17F, IL-21, IL-22) cytokines were associated with small-for-gestational-age babies. Our findings indicate that maternal HIV/ART is associated with distinct systemic cytokine profiles throughout pregnancy.

Figure 1

Systemic pro-inflammatory, anti-viral, Th1, Th2, Th17, pleiotropic and anti-inflammatory cytokines across pregnancy. (A) Pro-inflammatory (IL-1β, TNF-α, IP-10, IL-8), (B) anti-viral (IFNα2, IFNβ, IFNλ1, IFNλ2/3), (C) Th1 (IFNγ, IL-2, IL-12p70), (D) Th2 (IL-4, IL-5, IL-13), (E) Th17 (IL-17A, IL-17F, IL-21, IL-22) and (F) pleiotropic and anti-inflammatory (IL-6, IL-9, GM-CSF and IL-10 respectively) cytokines were measured in maternal plasma collected during the first (T1), second (T2) and third (T3) trimester. Data are presented as the percentage of samples in which cytokines were detected by multiplex cytokine assay. *P < 0.05.

Figure 2

Systemic cytokines across pregnancy in women living with HIV and HIV-negative women. (A,G) Pro-inflammatory (IL-1β, TNF-α, IP-10, IL-8), (B,H) anti-viral (IFNα2, IFNβ, IFNλ1, IFNλ2/3), (C,I) Th1 (IFNγ, IL-2, IL-12p70), (D,J) Th2 (IL-4, IL-5, IL-13), (E,K) Th17 (IL-17A, IL-17F, IL-21, IL-22) and (F,L) pleiotropic and anti-inflammatory (IL-6, IL-9, GM-CSF and IL-10 respectively) cytokines were measured in the maternal plasma collected during the first (T1), second (T2) and third (T3) trimester in women living with HIV (HIV+) (A–F) and HIV-negative women (HIV−) (G–L). Data are presented as the percentage of samples in which cytokines were detected by multiplex cytokine assay. *P < 0.05.

Figure 3

Systemic cytokines in women living with HIV versus HIV-negative women across pregnancy. (A) Pro-inflammatory (IL-1β, TNF-α, IP-10, IL-8), (B) anti-viral (IFNα2, IFNβ, IFNλ1, IFNλ2/3), (C) Th1 (IFNγ, IL-2, IL-12p70), (D) Th2 (IL-4, IL-5, IL-13), (E) Th17 (IL-17A, IL-17F, IL-21, IL-22) and (F) pleiotropic and anti-inflammatory (IL-6, IL-9, GM-CSF and IL-10 respectively) cytokines were measured in maternal plasma collected during the first (T1), second (T2) and third (T3) trimester in women living with HIV (HIV+) and HIV-negative women (HIV−). Data are presented as the percentage of samples in which cytokines were detected by multiplex cytokine assay. *P < 0.05.

Figure 4

Systemic cytokines across pregnancy in women who went on to deliver preterm (PTB) versus women who delivered at term. (A) Pro-inflammatory (IL-1β, TNF-α, IP-10, IL-8), (B) anti-viral (IFNα2, IFNβ, IFNλ1, IFNλ2/3), (C) Th1 (IFNγ, IL-2, IL-12p70), (D) Th2 (IL-4, IL-5, IL-13), (E) Th17 (IL-17A, IL-17F, IL-21, IL-22) and (F) pleiotropic and anti-inflammatory (IL-6, IL-9, GM-CSF and IL-10 respectively) cytokines were measured in maternal plasma collected during the first (T1), second (T2) and third (T3) trimester. Data are presented as the percentage of samples in which cytokines were detected by multiplex cytokine assay. *P < 0.05.

Figure 5

Systemic cytokines across pregnancy in women who went on to deliver small-for-gestational-age (SGA) infants versus women who delivered non-SGA infants. (A) Pro-inflammatory (IL-1β, TNF-α, IP-10, IL-8), (B) anti-viral (IFNα2, IFNβ, IFNλ1, IFNλ2/3), (C) Th1 (IFNγ, IL-2, IL-12p70), (D) Th2 (IL-4, IL-5, IL-13), (E) Th17 (IL-17A, IL-17F, IL-21, IL-22) and (F) pleiotropic and anti-inflammatory (IL-6, IL-9, GM-CSF and IL-10 respectively) cytokines were measured in maternal plasma collected during the first (T1), second (T2) and third (T3) trimester. Data are presented as the percentage of samples in which cytokines were detected by multiplex cytokine assay. *P < 0.05.

Figure 6

Systemic cytokine subgroups across pregnancy. (A) All women, (B) women living with HIV (HIV+), (C) HIV-negative women (HIV-), (D) HIV+ and HIV− women, (E) preterm (PTB) and term birth, and (F) small-for-gestational-age (SGA) and non-SGA infants. Pro-inflammatory (IL-1β, TNF-α, IP-10, IL-8), anti-viral (IFNα2, IFNβ, IFNλ1, IFNλ2/3), Th1 (IFNγ, IL-2, IL-12p70), Th2 (IL-4, IL-5, IL-13), Th17 (IL-17A, IL-17F, IL-21, IL-22) and pleiotropic (IL-6, IL-9, GM-CSF and IL-10 respectively) cytokines were measured in maternal plasma collected during the first (T1), second (T2) and third (T3) trimester in women living with HIV (HIV+) and HIV-negative (HIV−) women. Data are presented as the percentage of samples in which subgroups of cytokines were detected by multiplex cytokine assay. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.