Distinct cytokine profiles in late pregnancy in Ugandan people with HIV

Abstract

During pregnancy, multiple immune regulatory mechanisms establish an immune-tolerant environment for the allogeneic fetus, including cellular signals called cytokines that modify immune responses. However, the impact of maternal HIV infection on these responses is incompletely characterized. We analyzed paired maternal and umbilical cord plasma collected during labor from 147 people with HIV taking antiretroviral therapy and 142 HIV-uninfected comparators. Though cytokine concentrations were overall similar between groups, using Partial Least Squares Discriminant Analysis we identified distinct cytokine profiles in each group, driven by higher IL-5 and lower IL-8 and MIP-1α levels in pregnant people with HIV and higher RANTES and E-selectin in HIV-unexposed umbilical cord plasma (P-value < 0.01). Furthermore, maternal RANTES, SDF-α, gro $\alpha$ -KC, IL-6, and IP-10 levels differed significantly by HIV serostatus (P < 0.01). Although global maternal and umbilical cord cytokine profiles differed significantly (P < 0.01), umbilical cord plasma profiles were similar by maternal HIV serostatus. We demonstrate that HIV infection is associated with a distinct maternal plasma cytokine profile which is not transferred across the placenta, indicating a placental role in coordinating local inflammatory response. Furthermore, maternal cytokine profiles in people with HIV suggest an incomplete shift from Th2 to Th1 immune phenotype at the end of pregnancy.

Figure 1

The proportion of mother-baby pairs in which a specific cytokine was detected in neither plasma sample, only one plasma sample, or both paired plasma samples, by maternal HIV serostatus.

Figure 2

Cytokine concentrations of cytokines classified as Th1 (panel A) or Th2 (panel B) in maternal and umbilical cord plasma. Cytokine concentrations were natural log transformed.

Figure 3

The proportion of samples above 90th percentile for each cytokine concentration, stratified by maternal HIV serostatus, in maternal plasma (B) and umbilical cord plasma (C). Panel A represents what the figure would look like if HIV serostatus was not associated with extreme cytokine values, where each group would have 10% of samples fall above the 90th percentile.

Figure 4

Association between sum of log concentrations for Th1 and Th2 in maternal (panel A) and umbilical cord (panel B) blood. There is no overlap between the top 10 cases in maternal and umbilical cord blood. The 4 purple points indicate concentrations in the top 10 in both Th1 and Th2, 6 blue points indicate concentrations in the top 10 for Th1 only, and 6 pink points indicate concentrations in the top 10 in Th2 only.

Figure 5

Spearman correlations between cytokine concentrations in maternal plasma (A), umbilical cord plasma (B), and paired maternal and umbilical cord plasma (C). Values below the limit of detection were imputed as the limit of detection and included in computing the Spearman correlations. The proportion of samples that were below the limit of detection can be seen in Fig. 1.

Figure 6

Partial Least Squares Discriminant Analysis (PLSDA) demonstrating significant separation between cytokine profiles. A and B by maternal and umbilical cord plasma by maternal HIV status (A and B, P < 0.01) and significant separation between cytokine profiles of maternal and umbilical cord plasma (C and D, P < 0.01).

Figure 7

Partial Least Squares Discriminant Analysis (PLSDA) demonstrating significant separation between cytokine profiles of PPHIV and HIV-uninfected women (P = 0.02, A and B) and lack of significant separation between cytokine profiles of HIV-exposed and HIV-unexposed umbilical cord samples (P = 0.10, C and D).