Anti-HIV-1 Activity of Lactic Acid in Human Cervicovaginal Fluid.

David Tyssen,Jacques Ravel,Ying-Ying Wang,Gilda Tachedjian,Joshua A Hayward,Paul A Agius,Thomas R Moench,Richard A Cone,Muriel Aldunate,Kevin Delong,David W Pascual

doi:10.1128/msphere.00055-18

Abstract

Women of reproductive age with a Lactobacillus-dominated vaginal microbiota have a reduced risk of acquiring and transmitting HIV and a vaginal pH of ~4 due to the presence of ~1% (wt/vol) lactic acid. While lactic acid has potent HIV virucidal activity in vitro, whether lactic acid present in the vaginal lumen inactivates HIV has not been investigated. Here we evaluated the anti-HIV-1 activity of native, minimally diluted cervicovaginal fluid obtained from women of reproductive age (n = 20) with vaginal microbiota dominated by Lactobacillus spp. Inhibition of HIVBa-L was significantly associated with the protonated form of lactic acid in cervicovaginal fluid. The HIVBa-L inhibitory activity observed in the <3-kDa acidic filtrate was similar to that of the corresponding untreated native cervicovaginal fluid as well as that of clarified neat cervicovaginal fluid subjected to protease digestion. These ex vivo studies indicate that protonated lactic acid is a major anti-HIV-1 metabolite present in acidic cervicovaginal fluid, suggesting a potential role in reducing HIV transmission by inactivating virus introduced or shed into the cervicovaginal lumen.IMPORTANCE The Lactobacillus-dominated vaginal microbiota is associated with a reduced risk of acquiring and transmitting HIV and other sexually transmitted infections (STIs). Lactic acid is a major organic acid metabolite produced by lactobacilli that acidifies the vagina and has been reported to have inhibitory activity in vitro against bacterial, protozoan, and viral STIs, including HIV infections. However, the anti-HIV properties of lactic acid in native vaginal lumen fluids of women colonized with Lactobacillus spp. have not yet been established. Our study, using native cervicovaginal fluid from women, found that potent and irreversible anti-HIV-1 activity is significantly associated with the concentration of the protonated (acidic, uncharged) form of lactic acid. This work advances our understanding of the mechanisms by which vaginal microbiota modulate HIV susceptibility and could lead to novel strategies to prevent women from acquiring HIV or transmitting the virus during vaginal intercourse and vaginal birth.

Highlights

Women of reproductive age with a Lactobacillus-dominated vaginal microbiota have a reduced risk of acquiring and transmitting Human immunodeficiency virus (HIV) and a vaginal pH of ~4 due to the presence of ~1% lactic acid
Lactic acid is the major organic acid metabolite produced by vaginal Lactobacillus spp. and is dramatically depleted in women who are colonized with a diverse set of strict and facultative anaerobes and are at increased risk of acquiring or transmitting HIV [16, 17]
We found a strong and highly significant association between protonated lactic acid levels in native cervicovaginal fluid (CVF) and anti-HIV type 1 (HIV-1) activity against R5 HIV-1, even when accounting for lactate anion and low pH

Summary

Introduction

Women of reproductive age with a Lactobacillus-dominated vaginal microbiota have a reduced risk of acquiring and transmitting HIV and a vaginal pH of ~4 due to the presence of ~1% (wt/vol) lactic acid. The HIVBa-L inhibitory activity observed in the Ͻ3-kDa acidic filtrate was similar to that of the corresponding untreated native cervicovaginal fluid as well as that of clarified neat cervicovaginal fluid subjected to protease digestion These ex vivo studies indicate that protonated lactic acid is a major anti-HIV-1 metabolite present in acidic cervicovaginal fluid, suggesting a potential role in reducing HIV transmission by inactivating virus introduced or shed into the cervicovaginal lumen. Women lacking Lactobacillus spp., such as found in those with BV, have dramatically reduced levels of lactic acid [23,24,25] and elevated vaginal pH levels of Ͼ4.5 [12] These observations, together with the epidemiological evidence indicating that a Lactobacillus-dominated microbiota reduces a woman’s risk of acquiring or transmitting HIV [13,14,15], suggest that lactic acid represents a critical antimicrobial defense factor in the vagina

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Results

Conclusion