Abstract
Lactobacillus species, which dominate vaginal microbiota of healthy reproductive-age women, lower the risks of sexually transmitted infections, including the risk of human immunodeficiency virus (HIV) acquisition. The exact mechanisms of this protection remain to be understood. Here, we investigated these mechanisms in the context of human cervico-vaginal and lymphoid tissues ex vivo. We found that all six Lactobacillus strains tested in these systems significantly suppressed HIV type-1 (HIV-1) infection. We identified at least three factors that mediated this suppression: (i) Acidification of the medium. The pH of the undiluted medium conditioned by lactobacilli was between 3.8 and 4.6. Acidification of the culture medium with hydrochloric acid (HCl) to this pH in control experiments was sufficient to abrogate HIV-1 replication. However, the pH of the Lactobacillus-conditioned medium (CM) diluted fivefold, which reached ∼6.9, was also suppressive for HIV-1 infection, while in control experiments HIV-1 infection was not abrogated when the pH of the medium was brought to 6.9 through the use of HCl. This suggested the existence of other factors responsible for HIV-1 inhibition by lactobacilli. (ii) Lactic acid. There was a correlation between the concentration of lactic acid in the Lactobacillus-CM and its ability to suppress HIV-1 infection in human tissues ex vivo. Addition of lactic acid isomers D and L to tissue culture medium at the concentration that corresponded to their amount released by lactobacilli resulted in HIV-1 inhibition. Isomer L was produced in higher quantities than isomer D and was mostly responsible for HIV-1 inhibition. These results indicate that lactic acid, in particular its L-isomer, inhibits HIV-1 independently of lowering of the pH. (iii) Virucidal effect. Incubation of HIV-1 in Lactobacillus-CM significantly suppressed viral infectivity for human tissues ex vivo. Finally, lactobacilli adsorb HIV-1, serving as a sink decreasing the number of free virions. In summary, we found that lactobacilli inhibit HIV-1 replication in human tissue ex vivo by multiple mechanisms. Further studies are needed to evaluate the potential of altering the spectra of vaginal microbiota as an effective strategy to enhance vaginal health. Human tissues ex vivo may serve as a test system for these strategies.
Highlights
The vaginal microbiota of healthy reproductive-age women is generally dominated by Lactobacillus species (Ravel et al, 2011)
Fifteen Lactobacillus strains belonging to L. vaginalis, L. gasseri, and L. crispatus were evaluated for their capacity to colonize ex vivo tissue blocks
Minor variations depending on age, menstruation, sexual activity, use of medication, hygiene practice, etc. (Srinivasan and Fredricks, 2008) may affect the vaginal microbiota, healthy women of reproductive age are generally dominated by Lactobacillus species (Pavlova et al, 2002; Hyman et al, 2005; Ravel et al, 2011)
Summary
The vaginal microbiota of healthy reproductive-age women is generally dominated by Lactobacillus species (Ravel et al, 2011). Many hypotheses have been formulated regarding the protective effects of lactobacilli, the exact mechanisms of HIV inhibition by vaginal lactobacilli remain to be fully elucidated. These mechanisms seem to involve production of antiviral compounds such as lactic acid, hydrogen peroxide, bacteriocins, and lectins (Aldunate et al, 2013; Petrova et al, 2013). The inhibition of HIV transmission has been reported to be mediated by lactobacilli that affect vaginal epithelia, modulate bacterial vaginosis, or change local or systemic immune responses (Kaewsrichan et al, 2006; Reid et al, 2011)
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