Human Immunodeficiency Virus Type 1 Is Trapped by Acidic but Not by Neutralized Human Cervicovaginal Mucus

ABSTRACT To reliably infect a primate model for human immunodeficiency virus (HIV), ∼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 ∼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.

[1]  J. Hanes,et al.  Mucus-penetrating nanoparticles for drug and gene delivery to mucosal tissues. , 2009, Advanced drug delivery reviews.

[2]  Denis Wirtz,et al.  Micro- and macrorheology of mucus. , 2009, Advanced drug delivery reviews.

[3]  Samuel K. Lai,et al.  Altering Mucus Rheology to “Solidify” Human Mucus at the Nanoscale , 2009, PloS one.

[4]  A. Adimora,et al.  Bacterial vaginosis and HIV acquisition: a meta-analysis of published studies , 2008, AIDS.

[5]  M. Cohen.  Preventing sexual transmission of HIV. , 2007, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[6]  A. Cole,et al.  REVIEW ARTICLE: Antimicrobial Polypeptides are Key Anti‐HIV‐1 Effector Molecules of Cervicovaginal Host Defense , 2007, American journal of reproductive immunology.

[7]  T. Hope,et al.  Labeling HIV-1 virions with two fluorescent proteins allows identification of virions that have productively entered the target cell. , 2007, Virology.

[8]  Justin Hanes,et al.  Rapid transport of large polymeric nanoparticles in fresh undiluted human mucus , 2007, Proceedings of the National Academy of Sciences.

[9]  S. S. Olmsted,et al.  Low pH immobilizes and kills human leukocytes and prevents transmission of cell-associated HIV in a mouse model , 2005, BMC infectious diseases.

[10]  T. Schacker,et al.  HIV binding, penetration, and primary infection in human cervicovaginal tissue. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[11]  J. Sobel.  What's new in bacterial vaginosis and trichomoniasis? , 2005, Infectious disease clinics of North America.

[12]  O. Laeyendecker,et al.  Rates of HIV-1 transmission per coital act, by stage of HIV-1 infection, in Rakai, Uganda. , 2005, The Journal of infectious diseases.

[13]  Junghae Suh,et al.  Real-time multiple-particle tracking: applications to drug and gene delivery. , 2005, Advanced drug delivery reviews.

[14]  Christopher D Pilcher,et al.  Brief but efficient: acute HIV infection and the sexual transmission of HIV. , 2004, The Journal of infectious diseases.

[15]  John P. Moore,et al.  Inhibiting sexual transmission of HIV-1 infection , 2003, Nature Reviews Microbiology.

[16]  P. Reichelderfer,et al.  Recent observations on HIV type-1 infection in the genital tract of men and women. , 2003, AIDS.

[17]  S. S. Olmsted,et al.  Glycosidase and Proteinase Activity of Anaerobic Gram-Negative Bacteria Isolated From Women With Bacterial Vaginosis , 2003, Sexually transmitted diseases.

[18]  John P. Moore,et al.  Prevention of virus transmission to macaque monkeys by a vaginally applied monoclonal antibody to HIV-1 gp120 , 2003, Nature Medicine.

[19]  P. Hees,et al.  A Self-Sampling Method to Obtain Large Volumes of Undiluted Cervicovaginal Secretions , 2003, Sexually transmitted diseases.

[20]  Mardge H. Cohen,et al.  Determinants of HIV-1 shedding in the genital tract of women , 2001, The Lancet.

[21]  Christopher J. Miller,et al.  Simian Immunodeficiency Virus Rapidly Penetrates the Cervicovaginal Mucosa after Intravaginal Inoculation and Infects Intraepithelial Dendritic Cells , 2000, Journal of Virology.

[22]  M. Kazatchkine,et al.  Secretory Leukocyte Protease Inhibitor Inhibits Infection of Monocytes and Lymphocytes with Human Immunodeficiency Virus Type 1 but Does Not Interfere with Transcytosis of Cell-Associated Virus across Tight Epithelial Barriers , 2000, Clinical Diagnostic Laboratory Immunology.

[23]  S. Boris,et al.  Potential role of lactobacilli as prophylactic agents against genital pathogens. , 1999, AIDS patient care and STDs.

[24]  K. Whaley,et al.  Acid Production by Vaginal Flora In Vitro Is Consistent with the Rate and Extent of Vaginal Acidification , 1999, Infection and Immunity.

[25]  S. Hillier,et al.  The vaginal microbial ecosystem and resistance to HIV. , 1998, AIDS research and human retroviruses.

[26]  D. Anderson,et al.  T lymphocytes and macrophages, but not motile spermatozoa, are a significant source of human immunodeficiency virus in semen. , 1997, The Journal of infectious diseases.

[27]  L. Bélec,et al.  In vivo semen-associated pH neutralization of cervicovaginal secretions , 1997, Clinical and diagnostic laboratory immunology.

[28]  W. Saltzman,et al.  Leukocytes migrate through three-dimensional gels of midcycle cervical mucus. , 1994, Cellular immunology.

[29]  R. Coombs,et al.  Viricidal effect of Lactobacillus acidophilus on human immunodeficiency virus type 1: possible role in heterosexual transmission , 1991, The Journal of experimental medicine.

[30]  S. Meldrum,et al.  Continuous measurement by radio-telemetry of vaginal pH during human coitus. , 1973, Journal of reproduction and fertility.

[31]  Christopher J. Miller,et al.  Target cells in vaginal HIV transmission. , 2003, Microbes and infection.

[32]  P. Mårdh,et al.  Vaginitis and vaginosis. , 1991 .