The impact of antiretroviral therapy and Immunological factors on preterm and small for gestational age deliveries in HIV infected pregnant women.

Abstract

Introduction Antiretroviral therapy (ART) during pregnancy may be associated with an increased risk of adverse pregnancy outcomes, including preterm delivery (PTD) and small-for-gestational-age (SGA) but the underlying biological mechanisms remain unclear. Immune activation as well as the use of ART have been associated with adverse outcomes during pregnancy. We explored the association between adaptive and innate immune cell activation markers ex vivo in HIV-infected women initiating ART during or before pregnancy with PTD or SGA. Materials and methods Study participants were women living with HIV drawn from the PIMS cohort, based in Cape Town South Africa and initiated ART during pregnancy or conceived while on ART. Participants were enrolled at median 15 week’s gestation; and were analyzed for immune markers, matched on ART initiation timing (15 women initiated pre- and 15 during pregnancy). There were 30 PTD (delivery <37 weeks), 30 SGA (weight for age ≤10th centile) cases and 30 controls (term, weight for gestational age >25th centile) as outcomes. Immunological parameters were compared T cell activation, antigen presenting cell subsets, activation and function, regulatory T cell phenotypes and functions and plasma cytokine profiles. Results We found that CD8+ T cell, monocyte and dendritic cell activation were lower in PTD women initiating ART in pregnancy when compared to SGA cases and AGA controls over time. Classical (CD14+CD16-) and intermediate (CD14+CD16+) monocyte frequencies were higher in PTD than in SGA cases and AGA women initiating ART in pregnancy compared to those stable on ART. There was lower inflammatory monocyte (CD14dimCD16+) frequencies over time. Monocytes and mDCs but not pDCs showed higher levels of activation in patients initiating ART compared to those stable on ART. A lower activation of APCs (monocytes,

mDCs and pDCs) was associated with the PTD outcome. When APCs were stimulated with TLR ligands, a lower IFN-α production by monocytes following TLR4 was associated with PTD. A similar trend was also observed for TLR9 and TLR7/8 stimulation at some time points. Some plasma cytokine levels were higher in participants initiating treatment in pregnancy compared to those stable on ART but there was no link of cytokine levels with birth outcomes. Regulatory T cell frequencies did not differ between ART initiators and those stable on ART, did not change over the course of pregnancy and were not associated with pregnancy outcomes. Conclusion Overall, we noted that lower levels of monocyte activation and reduced functionality (IFN-α production) of monocytes in response to TLR stimulation were associated with PTD. A similar trend of reduced production of MIP-1β and TNF-α by monocytes was noted for PTD cases. This suggests that reduced responsiveness to antigen stimulation may be an underlying factor for PTD, especially for women initiating ART in pregnancy. The markers of immune activation described here may be potential biomarkers to identify women at risk for PTD. Our results also suggest that PTD and SGA have distinct underlying immunological determinants that warrant further investigation.