Date Published: November 21, 2013
Publisher: Public Library of Science
Author(s): Sandeep Gupta, Johannes S. Gach, Juan C. Becerra, Tran B. Phan, Jeffrey Pudney, Zina Moldoveanu, Sarah B. Joseph, Gary Landucci, Medalyn Jude Supnet, Li-Hua Ping, Davide Corti, Brian Moldt, Zdenek Hel, Antonio Lanzavecchia, Ruth M. Ruprecht, Dennis R. Burton, Jiri Mestecky, Deborah J. Anderson, Donald N. Forthal, Ronald C. Desrosiers.
The mechanisms by which human immunodeficiency virus type 1 (HIV-1) crosses mucosal surfaces to establish infection are unknown. Acidic genital secretions of HIV-1-infected women contain HIV-1 likely coated by antibody. We found that the combination of acidic pH and Env-specific IgG, including that from cervicovaginal and seminal fluids of HIV-1-infected individuals, augmented transcytosis across epithelial cells as much as 20-fold compared with Env-specific IgG at neutral pH or non-specific IgG at either pH. Enhanced transcytosis was observed with clinical HIV-1 isolates, including transmitted/founder strains, and was eliminated in Fc neonatal receptor (FcRn)-knockdown epithelial cells. Non-neutralizing antibodies allowed similar or less transcytosis than neutralizing antibodies. However, the ratio of total:infectious virus was higher for neutralizing antibodies, indicating that they allowed transcytosis while blocking infectivity of transcytosed virus. Immunocytochemistry revealed abundant FcRn expression in columnar epithelia lining the human endocervix and penile urethra. Acidity and Env-specific IgG enhance transcytosis of virus across epithelial cells via FcRn and could facilitate translocation of virus to susceptible target cells following sexual exposure.
Sexual transmission of HIV-1 requires that virus establish infection across genital tract or intestinal tissue. Sexually transmitted infections, other causes of inflammation, and localized trauma may allow susceptible CD4+ target cells at skin or mucosal surfaces to become directly exposed to secretions from infected sexual partners , . However, when skin and mucosa are intact, it remains unclear precisely how HIV-1 gains access to target cells. One possibility is that virus translocates between epithelial cells until susceptible cells are found either in or below the epithelium . Alternatively, Langerhans cells may sample the surface, acquire virus, and move it to areas of abundant target cells , . Finally, transcytosis of HIV-1 (i.e., movement through cells) has been studied as a potential mechanism to translocate virus from mucosal surfaces to deeper-lying CD4+ cells , , .
Female genital tract secretions are often acidic, and the secretions of HIV-infected individuals have antibody capable of coating virus contained in those secretions. These facts led us to explore the role of antibody and low pH on transcytosis of HIV-1 across epithelial cells. Our primary finding is that at acidic pH, IgG enhances transcytosis of HIV-1 clinical isolates, including transmitted/founder Env-pseudotyped strains. Moreover, antibody from both cervicovaginal and seminal fluid mediates enhanced transcytosis at low pH. The enhanced transcytosis is abrogated by blocking or knocking down FcRn, which is known to bind IgG and immune complexes at low pH and release them at neutral pH , . We also establish that virus translocated across epithelial cells after incubation with antibody at low pH remains infectious. Although neutralizing antibodies generally promote more transcytosis, the transcytosed virus is relatively less infectious than virus whose transcytosis is mediated by non-neutralizing antibodies. Finally, we demonstrate abundant FcRn protein expression in columnar epithelial cells of the human endocervix and penile urethra, suggesting that these sites could play a major role in FcRn-mediated immune complex transcytosis.