Seminal plasma induces inflammation and enhances HIV-1 replication in human cervical tissue explants

• Published in: PLoS pathogens Vol. 13; no. 5; p. e1006402
• Main Authors: Introini, Andrea, Boström, Stéphanie, Bradley, Frideborg, Gibbs, Anna, Glaessgen, Axel, Tjernlund, Annelie, Broliden, Kristina
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.05.2017; Public Library of Science (PLoS)
• Subjects: Acquired immune deficiency syndrome; Adult; AIDS; Biology and Life Sciences; CCL20 protein; CCR5 protein; Cervix; Cervix uteri; Cervix Uteri - immunology; Cervix Uteri - virology; Chemokine CCL1 - genetics; Chemokine CCL1 - immunology; Chemokine CCL20 - genetics; Chemokine CCL20 - immunology; Conditioning; Deoxyribonucleic acid; Disease prevention; Disease transmission; DNA; Electrochemical machining; Explants; Exposure; Female; Gene expression; Growth factors; Health aspects; HIV; HIV Infections - immunology; HIV Infections - transmission; HIV Infections - virology; HIV-1 - genetics; HIV-1 - physiology; Human immunodeficiency virus; Humans; Immunoregulation; In Vitro Techniques; Infections; Infectious diseases; Inflammation; Inflammatory response; Interleukin 1; Interleukin 6; Interleukin 7; Interleukin-6 - genetics; Interleukin-6 - immunology; Leukocytes; Leukocytes (neutrophilic); Male; Mathematical analysis; Mathematical models; Medicine; Medicine and Health Sciences; Middle Aged; Monocytes; Mucosa; Neutrophils; Peripheral blood; Plasma; Polymerase chain reaction; Recruitment; Replication; Rodents; Semen; Semen - immunology; Sexual intercourse; Social Sciences; Tumor necrosis factor; Uterus; Virology; Virus Replication; Viruses
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1006402

The most immediate and evident effect of mucosal exposure to semen in vivo is a local release of proinflammatory mediators accompanied by an influx of leukocytes into the female genital mucosa (FGM). The implication of such response in HIV-1 transmission has never been addressed due to limitations of currently available experimental models. Using human tissue explants from the uterine cervix, we developed a system of mucosal exposure to seminal plasma (SP) that supports HIV-1 replication. Treatment of ectocervical explants with SP resulted in the upregulation of inflammatory and growth factors, including IL-6, TNF, CCL5, CCL20, CXCL1, and CXCL8, and IL1A, CSF2, IL7, PTGS2, as evaluated by measuring protein levels in explant conditioned medium (ECM) and gene expression in tissue. SP treatment was also associated with increased recruitment of monocytes and neutrophils, as observed upon incubation of peripheral blood leukocytes with ECM in a transwell system. To evaluate the impact of the SP-mediated response on local susceptibility to HIV-1, we infected ectocervical explants with the CCR5-tropic variant HIV-1BaL either in the presence of SP, or after explant pre-incubation with SP. In both experimental settings SP enhanced virus replication as evaluated by HIV-1 p24gag released in explant culture medium over time, as well as by HIV-1 DNA quantification in explants infected in the presence of SP. These results suggest that a sustained inflammatory response elicited by SP soon after coitus may promote HIV-1 transmission to the FGM. Nevertheless, ectocervical tissue explants did not support the replication of transmitted/founder HIV-1 molecular clones, regardless of SP treatment. Our system offers experimental and analytical advantages over traditional models of HIV-1 transmission for the study of SP immunoregulatory effect on the FGM, and may provide a useful platform to ultimately identify new determinants of HIV-1 infection at this site.