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

Doctoral Degree. University of KwaZulu-Natal, Durban.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 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

Low Immune Activation in Early Pregnancy Is Associated With Preterm But Not Small-for-gestational-age Delivery in Women Infected With Human Immunodeficiency Virus Initiating Antiretroviral Therapy in Pregnancy: A Prematurity Immunology in HIV-infected Mothers and their Infants Study (PIMS) Case-control Study in Cape Town, South Africa.

BACKGROUND: Mechanisms underlying an association between human immunodeficiency virus (HIV) or antiretroviral therapy (ART) during pregnancy with risk of preterm delivery (PTD) and small-for-gestational-age (SGA) remain unclear. We explored the association between cellular immune activation and PTD or SGA in women with HIV initiating ART during or before pregnancy. METHODS: Women with HIV enrolled at median 15 weeks' gestation, were analyzed for immune markers, and matched on ART initiation timing (15 women initiated pre- and 15 during pregnancy). There were 30 PTD (delivery 25th percentile) as outcomes. Lymphocytes, monocytes, and dendritic cell populations and their activation status or functionality were enumerated by flow cytometry. RESULTS: PTD cases initiating ART in pregnancy showed decreased CD8+ T cell, monocyte, and dendritic cell activation; increased classical (CD14+CD16-) and intermediate (CD14+CD16+) monocyte frequencies; and decreased inflammatory monocytes (CD14dimCD16+) compared with SGA cases and term controls (all P < .05). Allowing for baseline viral load, the immune markers remained significantly associated with PTD but only in women initiating ART in pregnancy. Lower monocyte activation was predictive of PTD. TLR ligand-induced interferon-α and macrophage inflammatory protein-1β levels in monocytes were significantly lower in PTD women initiating ART in pregnancy. CONCLUSION: Low immune activation, skewing toward anti-inflammatory monocytes, and lower monocyte cytokine production in response to TLR ligand stimulation were associated with PTD but not SGA among women initiating ART in, but not before, pregnancy, suggesting immune anergy to microbial stimulation as a possible underlying mechanism for PTD in women initiating ART in pregnancy