Abstract
BackgroundPregnant women living with HIV infection (PWLWH) have elevated rates of preterm birth (PTB) in which HIV and cART are implicated. PWLWH also have a high prevalence of adverse vaginal microbiota, which associate with genital tract inflammation. The mechanism underlying PTB in PWLWH is unknown. We present the first data in PWLWH on genital-tract matrix-metalloproteinase-9(MMP-9), an important collagenase implicated in labour onset, and tissue inhibitor of metalloproteinases-1(TIMP-1) and explore correlations with local inflammation and vaginal bacteria.Material and MethodsCervical vaginal fluid (CVF) collected by a soft cup and high vaginal swabs (HVS) were obtained from PWLWH and HIV uninfected pregnant women (HUPW) at three antenatal time points. Maternal characteristics, combination antiretroviral therapy (cART) exposure, and pregnancy outcome were recorded. Concentrations of MMP-9, TIMP-1 and ten cytokines were measured by immunoassays. Vaginal microbiota composition was determined through 16S rRNA amplicon sequencing. MMP-9, TIMP-1 and cytokine concentrations were compared by HIV status, cART, and prematurity and in PWLWH correlations with polymorphonuclear leucocytes, cytokines and bacterial genera were explored.ResultsCVF was available for 50 PWLWH (108 samples) and 12 HUPW (20 samples) between gestation weeks 14-38. Thirty-six PWLWH conceived on cART and 14 initiated post-conception. There were five and one PTB outcomes in PWLWH and HUPW respectively. PWLWH had higher mean CVF concentrations of MMP-9 (p<0.001) and TIMP-1 (p=0.035) in the second trimester compared with HUPW with a similar trend in the third trimester. PWLWH also had higher CVF values of cytokines: IL-1β, IL-8, IL-12 and TNF-α in both trimesters compared to HUPW (p ≤ 0.003). In PWLWH, MMP-9 positively correlated with TIMP-1 (r=0.31, p=0.002) and CVF polymorphonuclear leucocytes (r=0.57, p=0.02). Correlations were observed between MMP-9 and three cytokines: IL-1β (r=0.61), IL-8 (r=0.57) and TNF-α (r=0.64), p<0.001, similarly for TIMP-1. Abundance of anaerobic pathobionts correlated with MMP-9: Gardnerella (r=0.44, p<0.001), Atopobium (r=0.33, p=0.005), and Prevotella genera (r=0.39, p<0.001). Conversely proportion of Lactobacillus genera negatively correlated with MMP-9 (rho=-0.46, p<0.001). MMP-9/TIMP-1 ratio increased with gestational age at sampling in PWLWH, but this was no longer significant after adjusting for confounders and no difference by prematurity was observed in this sub-study.ConclusionsHere we show strong correlations of MMP-9 to genital tract inflammation and sub-optimal bacterial genera in PWLWH indicating the ascending genital tract infection pathway may be a contributory mechanism to the high risk of PTB.
Highlights
Pregnant women living with HIV infection (PWLWH) are disproportionately affected by preterm birth (PTB) outcomes, with some cohorts experiencing two to four-fold the risk observed in the general population (Thorne et al, 2004; Short and Taylor, 2014; Wedi et al, 2016)
Thirty-six (72%) PWLWH conceived on combination antiretroviral therapy (cART) and 14 initiated cART post conception (27%). cART comprised a backbone of two nucleoside analogue reverse transcriptase inhibitors and one of the following third agents: a Protease Inhibitor (PI) n = 17 (34%); a Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI) n = 20 (40%); an Integrase Strand Transfer Inhibitor (INSTI) n = 10 (20%) and a third NRTI n = 3 (6%)
The main findings of these exploratory analyses include that PWLWH have high cervicovaginal fluid (CVF) concentrations of matrix metalloproteinase 9 (MMP-9), tissue inhibitor metalloproteinase-1 (TIMP-1), pro-inflammatory cytokines and MMP-9/TIMP-1 ratios in comparison to the HIV uninfected pregnant women (HUPW) participants
Summary
Pregnant women living with HIV infection (PWLWH) are disproportionately affected by PTB outcomes, with some cohorts experiencing two to four-fold the risk observed in the general population (Thorne et al, 2004; Short and Taylor, 2014; Wedi et al, 2016). The aetiology of this phenomenon is unclear but the successful use of combination antiretroviral therapy (cART) to prevent mother to child transmission of HIV (PMTCT) has not had the same impact on high rates of PTB and may increase risk of this complication (Thorne et al, 2004). We present the first data in PWLWH on genital-tract matrix-metalloproteinase-9(MMP-9), an important collagenase implicated in labour onset, and tissue inhibitor of metalloproteinases-1(TIMP-1) and explore correlations with local inflammation and vaginal bacteria
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