Lactobacillus-Depleted Vaginal Microbiota in Pregnant Women Living With HIV-1 Infection Are Associated With Increased Local Inflammation and Preterm Birth

Abstract

BackgroundPregnant women living with HIV-1 infection (PWLWH) have an elevated risk of preterm birth (PTB) of unknown aetiology, which remains after successful suppression of HIV. Women at high risk for HIV have a common bacterial profile which has been associated with poor birth outcomes. We set out to explore factors associated with gestational age at delivery of PWLWH in a UK population.MethodsProspective study of PWLWH (n = 53) in whom the vaginal microbiota and cervicovaginal cytokine milieu were assessed using metataxonomics and multiplexed immunoassays, respectively. Cross-sectional characterisation of vaginal microbiota in PWLWH were compared with 22 HIV uninfected pregnant women (HUPW) at a similar second trimester timepoint. Within PWLWH the relationships between bacterial composition, inflammatory response, and gestational age at delivery were explored.FindingsThere was a high rate of PTB among PWLWH (12%). In the second trimester the vaginal microbiota was more diverse in PWLWH than in HUPW (Inverse Simpson Index, p = 0.0004 and Species Observed, p = 0.009). PWLWH had a lower prevalence of L. crispatus dominant vaginal microbiota group (VMB I, 15 vs 54%) than HUPW and higher prevalence of L. iners dominant (VMB III, 36 vs 9% and VMB IIIB, 15 vs 5%) and mixed anaerobes (VMB IV, 21 vs 0%). Across the second and third trimesters in PWLWH, VMB III/IIIB and IV were associated with PTB and with increased local inflammation [cervicovaginal fluid (CVF) cytokine concentrations in upper quartile]. High bacterial diversity and anaerobic bacterial abundance were also associated with CVF pro-inflammatory cytokines, most notably IL-1β.InterpretationThere is an association between local inflammation, vaginal dysbiosis and PTB in PWLWH. Understanding the potential of antiretroviral therapies to influence this cascade will be important to improve birth outcomes in this population.

Vaginal bacterial load in the second trimester is associated with early preterm birth recurrence: a nested case–control study

“…3 In 2014, 16S ribosomal RNA (16S rRNA) sequencing was first used to assess the relation between the bacterial vaginal microbiota (VMB) and PTB. 4 Since then, over 3000 pregnant women have been assessed in 18 studies [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21] (Appendix S1, Table S1). The majority of these studies have suggested a contribution of the VMB composition to PTB, but results have been inconsistent.…”

Vaginal Microbiota, Genital Inflammation and Extracellular Matrix Remodelling Collagenase: MMP-9 in Pregnant Women With HIV, a Potential Preterm Birth Mechanism Warranting Further Exploration

“…The pathologic mechanism of PTB in PWLWH is unclear. We hypothesize the elevated risk of PTB is the result of an inflammatory process driven by alternations in: the balance of cytokines at the maternal foetal interface ( Fiore et al., 2006 ; Short and Taylor, 2014 ; Short et al., 2021 ) and dysregulation of immune activation of maternal T cells ( Short et al., 2017 ) to promote local immune cell infiltration in the female reproductive tract; both of which are influenced by local vaginal microbiota composition ( Short et al., 2013 ; Anahtar et al., 2015 ; Short et al., 2021 ).…”

“…We and others have described that PWLWH in European and African settings have a microbiota either dominated by Lactobacillus iners or with a diverse anaerobic bacteria community structure ( Price et al., 2019 ; Gudza-Mugabe et al., 2020 ; Short et al., 2021 ). Lactobacillus single species dominance in pregnancy, particularly L. crispatus , is associated with term birth outcomes whereas L. iners species dominance, the least stable Lactobacillus community structure, and mixed anaerobes are associated with PTB ( Kindinger et al., 2017 ; Brown et al., 2018 ; Elovitz et al., 2019 ; Fettweis et al., 2019 ).…”

“…Lactobacillus single species dominance in pregnancy, particularly L. crispatus , is associated with term birth outcomes whereas L. iners species dominance, the least stable Lactobacillus community structure, and mixed anaerobes are associated with PTB ( Kindinger et al., 2017 ; Brown et al., 2018 ; Elovitz et al., 2019 ; Fettweis et al., 2019 ). Within our London HIV PTB study cohort all PTB occurred in women with these adverse vaginal microbiota groups ( Short et al., 2021 ). How these bacteria exert their effects on downstream pathways to trigger labour is not fully elucidated.…”

“…Here we explore MMP-9, TIMP-1 and cytokine concentrations, and local polymorphonuclear leucocytes in a subgroup of PWLWH from the London HIV PTB study for whom cervicovaginal fluid (CVF) and high vaginal bacterial metataxonomic data were available and examine the association with lower genital tract microbiota composition. The full characterization of the vaginal microbiota of PWLWH from the London HIV Preterm birth study has been described previously ( Short et al., 2021 ). These data have been used for correlation analyses with CVF MMP-9, TIMP-1 and cytokine concentrations.…”