Title: The immunological basis for increased Preterm Birth in HIV-1 infected pregnant women and the influence of different classes of antiretroviral therapy
Funder: The Academy of Medical Sciences

Abstract: The main aim of this proposal is to better understand the underlying cause of the excess preterm birth experienced by PWLWH, up to 40% in some cohorts, compared to the general UK population rate of 5-6%. The objectives of the proposed work are to further describe the vaginal microbiota of PWLWH in the HIV PTB study compared to HIV uninfected pregnant women (HUP), both in terms of microbiota community structure in addition to the total bacterial load. The second objective is to more fully appreciate the downstream pathways of inflammation associated with adverse pathobionts and how these interact with the mechanistic pathways that trigger labour through quantification of cervicovaginal: cytokines, leukocyte activation markers, antimicrobial and extracellular matrix remodelling proteins and mRNA expression. A third objective is to understand how these local female genital inflammatory pathways may be modulated by innate and adaptive immune cells by characterisation of T cell subsets, particularly T regulatory cells, and Innate Lymphoid Cells. Finally, we propose to examine the direct and indirect effect of antiviral therapy on the vaginal microbiota and how this may be the link behind their implicated causality in excess preterm birth experienced by PWLWH by conducting minimum inhibitory concentration bacterial culture work with common vaginal species +/- biofilms and conducting statistical mixed effect factorial modelling.

Lay abstract: Pregnant women living with HIV infection (PWLWH) are at high risk of delivering their babies early (preterm birth, PTB, less than 37 weeks). It is estimated that PWLWH have double the usual risk of pregnant women. Researchers have identified that the antiviral therapy that these mothers need for their and their babies' health, to prevent HIV infection in babies, actually increases rates of PTB. Our research has identified that PWLWH has different vaginal bugs (bacteria) from uninfected pregnant women and that these bacteria are associated with inflammation (increased immune system activity). We believe that the antiviral drugs taken during pregnancy may have a negative effect on the vaginal bacteria, making the bacteria present more likely to be ones associated with inflammation and that this inflammation signals to the mother’s body to start labour before time. We have set up a study collecting samples of genital fluid (cervicovaginal fluid, CVF) and blood from pregnant women with and without HIV during their second and third stages of pregnancy. We will use CVF to look at which bacteria are present and how the immune system reacts to these bacteria. We will also set up experiments to look at how the commonly found bacteria react to the most used antiviral drugs. We will also examine the blood cells of the immune system to see how these relate to the inflammation in the genital tract. Finally, we will put all these factors together to establish a model of how preterm birth occurs in these women.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION;REPRODUCTIVE HEALTH AND CHILDBIRTH