Lisa Bebell, MD, MS

Distinct cytokine profiles in late pregnancy in Ugandan people with HIV

Lisa M. Bebell1*, Joseph Ngonzi2, Audrey Butler3, Elias Kumbakumba4, Julian Adong4, Carolin Loos5, Adeline A. Boatin6, Ingrid V. Bassett7, Mark J. Siedner7, Paige L. Williams8, Heather Mattie8, Bethany Hedt-Gauthier8,9, Katharine F.B. Correia10, Erin Lake8†, Galit Alter5†

1Massachusetts General Hospital Division of Infectious Diseases, Medical Practice Evaluation Center and Center for Global Health, Boston, MA, USA
2Mbarara University of Science and Technology Department of Obstetrics and Gynaecology, Mbarara, Uganda
3State University of New York Upstate Medical University, NY, USA 
4Mbarara University of Science and Technology Department of Paediatrics and Child Health, Mbarara, Uganda
5Ragon Institute of MGH, MIT and Harvard, Cambridge MA, USA
6Massachusetts General Hospital Department of Obstetrics and Gynecology and Center for Global Health, Boston, MA, USA
7Massachusetts General Hospital Division of Infectious Diseases and Medical Practice Evaluation Center, Boston, MA, USA
8Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA
9Department of Global Health and Social Medicine, Harvard Medical School, Boston, MA, USA 
10Department of Mathematics & Statistics, Amherst College, Amherst, MA, USA and Biostatistics, Massachusetts General Hospital, Boston, MA, United States

During pregnancy, multiple immune regulatory mechanisms are activated to 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 pregnant people with HIV (PPHIV) taking antiretroviral therapy (ART) and 142 HIV-uninfected comparators. We used multiplex immunoassays to measure 27 chemokines and inflammatory cytokines in paired maternal and umbilical cord plasma and grouped cytokine into T-helper 1 (Th1) and T-helper 2 (Th2) phenotypes. We built Partial Least Squares Discriminant Analysis (PLSDA) models to assess how cytokines differed between maternal and umbilical cord plasma, and HIV serostatus/exposure.

All PPHIV reported taking ART, 54% started ART preconception, and 28% had detectable HIV viremia. Among those with viremia, median HIV viral load was 718 copies/mL, and median CD4 T-cell count was 426 cells/mm3. Overall cytokine levels were similar between maternal HIV serostatus and viremia groups. P-selectin, IL-β, IL-12p70, and IL-13 were the most frequently detected cytokines in both maternal and umbilical cord plasma (>90% of samples). GM-CSF, IL-4, and TNF-α were more frequently detected in maternal than umbilical cord plasma, whereas IL-6 and SDF-α were more frequently detected in umbilical cord plasma. IL-1α, IFN-α, and Groα KC were the least frequently detected (<30% of samples). Using PLSDA, we identified distinct cytokine profiles in each maternal HIV serostatus/umbilical cord exposure group, driven by higher IL-5 and lower IL-8 and MIP-1α levels in PPHIV, and higher RANTES and E-selectin in HIV-unexposed umbilical cord plasma (P-value <0.01). Furthermore, maternal RANTES, SDF-α, groα -KC, IL-6, and IP-10 levels differed by HIV serostatus (P <0.01). Although global maternal and umbilical cord cytokine profiles differed significantly (P <0.01), umbilical cord plasma profiles did not differ by maternal HIV serostatus.

HIV infection was associated with a distinct maternal plasma cytokine profile which was not transferred across the placenta, indicating a placental role in coordinating local inflammatory response. Furthermore, cytokine profiles in PPHIV suggested an incomplete shift from Th2 to Th1 phenotype at the end of pregnancy.