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. 2015 Oct 6;6(5):e01084-15.
doi: 10.1128/mBio.01084-15.

Enhanced Trapping of HIV-1 by Human Cervicovaginal Mucus Is Associated With Lactobacillus crispatus-Dominant Microbiota

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Free PMC article

Enhanced Trapping of HIV-1 by Human Cervicovaginal Mucus Is Associated With Lactobacillus crispatus-Dominant Microbiota

Kenetta L Nunn et al. mBio. .
Free PMC article

Abstract

Cervicovaginal mucus (CVM) can provide a barrier that precludes HIV and other sexually transmitted virions from reaching target cells in the vaginal epithelium, thereby preventing or reducing infections. However, the barrier properties of CVM differ from woman to woman, and the causes of these variations are not yet well understood. Using high-resolution particle tracking of fluorescent HIV-1 pseudoviruses, we found that neither pH nor Nugent scores nor total lactic acid levels correlated significantly with virus trapping in unmodified CVM from diverse donors. Surprisingly, HIV-1 was generally trapped in CVM with relatively high concentrations of d-lactic acid and a Lactobacillus crispatus-dominant microbiota. In contrast, a substantial fraction of HIV-1 virions diffused rapidly through CVM with low concentrations of d-lactic acid that had a Lactobacillus iners-dominant microbiota or significant amounts of Gardnerella vaginalis, a bacterium associated with bacterial vaginosis. Our results demonstrate that the vaginal microbiota, including specific species of Lactobacillus, can alter the diffusional barrier properties of CVM against HIV and likely other sexually transmitted viruses and that these microbiota-associated changes may account in part for the elevated risks of HIV acquisition linked to bacterial vaginosis or intermediate vaginal microbiota.

Importance: Variations in the vaginal microbiota, especially shifts away from Lactobacillus-dominant microbiota, are associated with differential risks of acquiring HIV or other sexually transmitted infections. However, emerging evidence suggests that Lactobacillus iners frequently colonizes women with recurring bacterial vaginosis, raising the possibility that L. iners may not be as protective as other Lactobacillus species. Our study was designed to improve understanding of how the cervicovaginal mucus barrier against HIV may vary between women along with the vaginal microbiota and led to the finding that the vaginal microbiota, including specific species of Lactobacillus, can directly alter the diffusional barrier properties of cervicovaginal mucus. This work advances our understanding of the complex barrier properties of mucus and highlights the differential protective ability of different species of Lactobacillus, with Lactobacillus crispatus and possibly other species playing a key role in protection against HIV and other sexually transmitted infections. These findings could lead to the development of novel strategies to protect women against HIV.

Figures

FIG 1
FIG 1
(A) Representative traces of mobile versus trapped HIV-1 virions compared to PS-PEG nanoparticles that are mucoinert and readily diffuse through CVM and compared to PS-COOH nanoparticles that are mucoadhesive and trapped in CVM. (B to G) HIV-1 mobility measured by average effective diffusivity (Deff) (B to D) values or fraction of mobile virions (E to G) versus pH (B and E), Nugent score (C and F), or total LA (D and G) for n = 31 CVM samples with a pH level of >4.2 (n = 12) or ≤4.2 (n = 19). Dashed lines indicate the cutoff between samples with a significant mobile HIV-1 population (≥10% mobile) and those in which HIV-1 is largely trapped (<10% mobile). w/v, weight/volume.
FIG 2
FIG 2
HIV-1 mobility measured by average effective diffusivity (Deff) (A to C) values or fraction of mobile virions (D to F) versus D-LA (A and D), L-LA (B and E), or D:L ratio (C and F) for n = 31 CVM samples with a pH level of >4.2 (n = 12) or ≤4.2 (n = 19). Dashed lines indicate the cutoff between samples with a significant mobile HIV-1 population (≥10% mobile) and those in which HIV-1 is largely trapped (<10% mobile).
FIG 3
FIG 3
(A) 16S rRNA sequencing and RNAseq analysis of CVM specimens reveals groups with distinct vaginal microbiotas: L. crispatus-dominant microbiota (group 1), L. iners-dominant microbiota (group 2), and microbiota containing a significant fraction of G. vaginalis (group 3). The color bar indicates the abundance of different bacterial species as a proportion of all species in the sample. Annulus charts depict the average distributions of the bacterial population across species of lactobacilli, Gardnerella vaginalis, and other species within each group. Donor identification numbers (IDs) are indicated to allow comparisons to the biochemical characterization data and bacterial abundance values in Tables S1 and S2 in the supplemental material. (B) HIV-1 mobility measured by average effective diffusivity (Deff) values or fraction of mobile virions in CVM samples within each group. The dashed line indicates the cutoff between samples with a significant mobile HIV-1 population (≥10% mobile) and those in which HIV-1 is largely trapped (<10% mobile). (C) Average pH, Nugent score, total LA, D-LA, L-LA, and D:L ratio for CVM samples within each group. *, P < 0.05 (statistically significant difference between group 1 and groups 2 and 3).
FIG 4
FIG 4
Comparison of average effective diffusivity (Deff) values for mucoinert synthetic beads (PS-PEG) (A), HIV-1 ΔEnv pseudovirus (B), or PS-COOH (C) to that of HIV-1 in native CVM. Data represent n = 8, 13, and 8 distinct CVM samples for PS-PEG, HIV-1 ΔEnv, and PS-COOH, respectively. Lines connect pairs of data points for the same sample.
FIG 5
FIG 5
Comparison of average effective diffusivity values for HIV-1 in native versus neutralized (pH 7) CVM. Data represent n = 31 distinct CVM samples. Lines connect pairs of data points for the same sample.

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References

    1. Gipson IK. 2001. Mucins of the human endocervix. Front Biosci 6:D1245–D1255. doi:10.2741/Gipson. - DOI - PubMed
    1. Kieweg SL, Geonnotti AR, Katz DF. 2004. Gravity-induced coating flows of vaginal gel formulations: in vitro experimental analysis. J Pharm Sci 93:2941–2952. doi:10.1002/jps.20194. - DOI - PubMed
    1. Kieweg SL, Katz DF. 2006. Squeezing flows of vaginal gel formulations relevant to microbicide drug delivery. J Biomech Eng 128:540–553. doi:10.1115/1.2206198. - DOI - PubMed
    1. Odeblad E. 1964. Intracavitary circulation of aqueous material in the human vagina. Acta Obstet Gynecol Scand 43:360–368. doi:10.3109/00016346409162686. - DOI - PubMed
    1. Wagner G, Levin RJ. 1980. Electrolytes in vaginal fluid during the menstrual cycle of coitally active and inactive women. J Reprod Fertil 60:17–27. doi:10.1530/jrf.0.0600017. - DOI - PubMed

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