Human immunodeficiency virus type 1 is trapped by acidic but not by neutralized human cervicovaginal mucus - PubMed (original) (raw)

Human immunodeficiency virus type 1 is trapped by acidic but not by neutralized human cervicovaginal mucus

Samuel K Lai et al. J Virol. 2009 Nov.

Abstract

To reliably infect a primate model for human immunodeficiency virus (HIV), approximately 10,000-fold more virus must be delivered vaginally than intravenously. However, the vaginal mechanisms that help protect against HIV are poorly understood. Here, we report that human cervicovaginal mucus (CVM), obtained from donors with normal lactobacillus-dominated vaginal flora, efficiently traps HIV, causing it to diffuse more than 1,000-fold more slowly than it does in water. Lactobacilli acidify CVM to pH approximately 4 by continuously producing lactic acid. At this acidic pH, we found that lactic acid, but not HCl, abolished the negative surface charge on HIV without lysing the virus membrane. In contrast, in CVM neutralized to pH 6 to 7, as occurs when semen temporarily neutralizes the vagina, HIV maintained its native surface charge and diffused only 15-fold more slowly than it would in water. Thus, methods that can maintain both a high lactic acid content and acidity for CVM during coitus may contribute to both vaginal and penile protection by trapping HIV before it can reach target cells. Our results reveal that CVM likely plays an important but currently unappreciated role in decreasing the rate of HIV sexual transmission.

PubMed Disclaimer

Figures

FIG. 1.

FIG. 1.

Transport of GFP-tagged HIV VLPs in CVM. (A) Sample 20-s trajectories of HIV VLPs, with mean square displacement values within 1 standard error of the ensemble mean square displacement in neutral and acidic CVM samples. (B) Arithmetic averages of ensemble geometric mean square displacement (

) as a function of τ. The data represent six experiments with CVM samples from different donors for acidic and neutral mucus (n ≈ 100 VLPs per experiment). The error bars indicate standard errors.

FIG. 2.

FIG. 2.

Distributions of the average speeds of individual HIV VLPs, as a percentage of the total number of HIV VLPs, in acidic and neutral CVM at a time scale of 1 s. The geometric mean of the distributions is represented by an empty arrow for HIV VLPs in acidic CVM and by a filled arrow for HIV VLPs in neutral CVM. The asterisk represents statistical significance with a one-sided Student t test (P ≤ 0.05).

FIG. 3.

FIG. 3.

Zeta potentials of HIV VLPs incubated in 0.3% (wt/wt) lactic acid or 10 mM NaCl at pH 4.0 and 7.0.

FIG. 4.

FIG. 4.

Western blot detection of HIV type 1 envelope and capsid proteins in virions. Infectious viruses were exposed for 1 h to 0.3% or 1% lactic acid (LA) solution in PBS at pH 4.0 or pH 7.0. The virions were then concentrated by ultracentrifugation through a 20% sucrose cushion and analyzed by Western blotting using anti-gp120 (ID6) and anti-p24 (AG3.0) antibodies.

FIG. 5.

FIG. 5.

Estimated fraction of the initial HIV dose present in a semen layer that could penetrate across a layer of neutral or acidic CVM and reach the underlying epithelium over time. The speeds of individual HIV particles were obtained from particle-tracking results, and the fraction of particles that reached the epithelial cell layer was estimated using Fick's law. (Inset) Schematic of the model, in which a layer of HIV-containing semen sits on top of a layer of unstirred, “firmly adherent” CVM overlying the cervicovaginal epithelium.

References

    1. Atashili, J., C. Poole, P. M. Ndumbe, A. A. Adimora, and J. S. Smith. 2008. Bacterial vaginosis and HIV acquisition: a meta-analysis of published studies. AIDS 22:1493-1501. - PMC - PubMed
    1. Barbes, C., and S. Boris. 1999. Potential role of lactobacilli as prophylactic agents against genital pathogens. AIDS Patient Care STDS 13:747-751. - PubMed
    1. Boskey, E. R., T. R. Moench, P. S. Hees, and R. A. Cone. 2003. A self-sampling method to obtain large volumes of undiluted cervicovaginal secretions. Sex. Transm. Dis. 30:107-109. - PubMed
    1. Boskey, E. R., K. M. Telsch, K. J. Whaley, T. R. Moench, and R. A. Cone. 1999. Acid production by vaginal flora in vitro is consistent with the rate and extent of vaginal acidification. Infect. Immun. 67:5170-5175. - PMC - PubMed
    1. Campbell, E. M., O. Perez, M. Melar, and T. J. Hope. 2007. Labeling HIV-1 virions with two fluorescent proteins allows identification of virions that have productively entered the target cell. Virology 360:286-293. - PMC - PubMed

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources