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Epithelial Cells Inhibit HIV-1 Transcytosis Across Human HIV-1

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Epithelial Cells Inhibit HIV-1 Transcytosis Across Human HIV-1 Mucosal and Plasma IgA from HIV-1-Exposed Uninfected Individuals Inhibit HIV-1 Transcytosis Across Human Epithelial Cells This information is current as of September 30, 2021. Claudia Devito, Kristina Broliden, Rupert Kaul, Lennart Svensson, Kari Johansen, Peter Kiama, Joshua Kimani, Lucia Lopalco, Stefania Piconi, Job J. Bwayo, Francis Plummer, Mario Clerici and Jorma Hinkula J Immunol 2000; 165:5170-5176; ; Downloaded from doi: 10.4049/jimmunol.165.9.5170 http://www.jimmunol.org/content/165/9/5170 http://www.jimmunol.org/ References This article cites 39 articles, 10 of which you can access for free at: http://www.jimmunol.org/content/165/9/5170.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on September 30, 2021 • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2000 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Mucosal and Plasma IgA from HIV-1-Exposed Uninfected Individuals Inhibit HIV-1 Transcytosis Across Human Epithelial Cells1 Claudia Devito,* Kristina Broliden,2* Rupert Kaul,† Lennart Svensson,‡ Kari Johansen,‡ Peter Kiama,† Joshua Kimani,† Lucia Lopalco,§ Stefania Piconi,¶ Job J. Bwayo,† Francis Plummer,†ʈ Mario Clerici,3 and Jorma Hinkula‡ HIV-1-specific IgA has been described in the genital tract and plasma of HIV-1 highly exposed, persistently seronegative (HEPS) individuals, and IgA from these sites has been shown to neutralize HIV-1. This study examines the ability of IgA isolated from HEPS individuals to inhibit transcytosis across a tight epithelial cell layer. A Transwell system was established to model HIV-1 infection across the human mucosal epithelium. The apical-basolateral transcytosis of primary HIV-1 isolates across this mucosal Downloaded from model was examined in the presence and the absence of IgA isolated from the genital tract, saliva, and plasma of HEPS individuals enrolled in both a sex worker cohort in Nairobi, Kenya, and a discordant couple cohort in Italy. In the absence of IgA, HIV-1 primary isolates were actively transported across the epithelial membrane and were released on the opposite side of the barrier. These transcytosed HIV-1 particles retained their ability to infect human mononuclear cells. However, IgA purified from the mucosa and plasma of HEPS individuals was able to inhibit HIV-1 transcytosis. Inhibition was seen in three of six cervicovaginal fluid samples, five of 10 saliva samples, and three of six plasma samples against at least one of the two primary HIV-1 isolates http://www.jimmunol.org/ tested. IgA from low risk, healthy control subjects had no inhibitory effect on HIV-1 transcytosis. The ability of mucosal and plasma IgA to inhibit HIV-1 transcytosis across the mucosal epithelium may represent an important mechanism for protection against the sexual acquisition of HIV-1 infection in HEPS individuals. The Journal of Immunology, 2000, 165: 5170–5176. ore than 90% of global HIV-1 transmission occurs pathogens. While innate immune factors and cells constitute the across a mucosal surface (1, 2). This may be the gen- first line of defense against invading micro-organisms, Ag-specific M ital tract mucosa, as in the case of heterosexual trans- humoral and cell-mediated responses are generally required for a mission of HIV-1, or the oropharyngeal mucosa, as in the case of partial or full protection from infection (4). by guest on September 30, 2021 breast milk transmission. Although transmission across intact mu- Some individuals in high risk groups appear to resist HIV in- cosal surfaces can occur, surface abrasions and breaks in the in- fection despite multiple repeated exposure to the virus (5–7). tegrity of the mucosal epithelium increase the risk of infection. These highly exposed, persistently seronegative (HEPS)4 individ- Sexually transmitted diseases and other factors amplifying inflam- uals remain HIV IgG negative as tested by Western blotting and matory T cell populations in regional mucosal sites also exacerbate lack detectable HIV RNA and HIV DNA as measured by PCR. HIV transmission (3). The mucosal immune system protects the Furthermore, they have no clinical or laboratory signs of immu- epithelium and underlying tissues and organs from environmental nodeficiency. It has been suggested that HIV-specific Th and CTL, ␤ chemokines, and a homozygous deletion of the CCR5 receptor confer partial protection against infection in these individuals (5– *Department of Clinical Virology, Karolinska Institute, Huddinge University Hospi- 9). Recently, we reported that they also have mucosal HIV-specific tal, Stockholm, Sweden; †Department of Medical Microbiology, University of ‡ IgA (7, 10) and that these Abs could neutralize primary HIV-1 Nairobi, Nairobi, Kenya; Department of Clinical Virology, Swedish Institute for 5 Infectious Disease Control, Microbiology and Tumor Biology Center, Karolinska isolates in an assay using PBMCs as target cells (11). Institute, Stockholm, Sweden; §Immunobiology of HIV Unit, San Raffaele Scientific In the present report the functional properties of mucosal (cer- Institute, Milan, Italy; ¶Division of Infectious Diseases, L. Sacco Hospital, Disp-Lita Viaeba, Milan, Italy; and ʈDepartment of Medical Microbiology, University of Mani- vicovaginal fluid and saliva) and systemic (plasma) IgA Abs from toba, Winnipeg, Canada HEPS individuals were further explored in a model of HIV-1 Received for publication March 27, 2000. Accepted for publication August 2, 2000. transcytosis across a tight human epithelial cell layer. Polarized The costs of publication of this article were defrayed in part by the payment of page epithelial cells have a plasma membrane that is separated into charges. This article must therefore be hereby marked advertisement in accordance clearly distinct domains by tight junctions: the apical domain, with 18 U.S.C. Section 1734 solely to indicate this fact. which faces the lumen, and the basolateral domain, which faces the 1 This work was supported by grants from the European Community “Concerted serosal side and the internal milieu (12). Transcytosis is the char- Action BMH4-CT97-2055” (to M.C. and K.B.); The Swedish Physicians Against AIDS Research Foundation (to K.B.); Instituto Superiore di Sanita`, X Progetto AIDS acteristic pathway of membrane trafficking, allowing selective and Grant 40.A.0.58 (to L.L.) and Grant 9403-34 (to M.C. and S.P.); the Medical Re- rapid transcellular transport from the apical to the basolateral pole search Council of Canada (to R.K.; fellowship to F.P.; Senior Scientist Award GR13301 to F.P.); Swedish Medical Research Council Grant 06X-13030 (to J.H.); and Rockefeller Foundation Grant RF96034 (to F.P.). 2 Address correspondence and reprint requests to Dr. Kristina Broliden, Department 4 Abbreviations used in this paper: HEPS, highly exposed, persistently seronegative; of Clinical Virology, F68, Karolinska Institute, Huddinge University Hospital, S-141 CVF, cervicovaginal fluid; NSI, nonsyncytium-inducing; SI, syncytium-inducing. 86 Stockholm, Sweden. E-mail address: [email protected] 5 C. Devito, J. Hinkula, R. Kaul, L. Lopalco, C. Barass, S. Piconi, D. Trabattoni, J. J. 3 Current address: Chair of Immunology, University of Milan, Via GB Grassi 74, Bwayo, F. Plummer, M. Clerici, et al. Mucosal and plasma IgA from HIV-exposed 20157 Milan, Italy. seronegative individuals neutralize primary HIV-1 isolates. Submitted for publication. Copyright © 2000 by The American Association of Immunologists 0022-1767/00/$02.00 The Journal of Immunology 5171 of this epithelium (12, 13). In elegant studies, Bomsel et al. (14) D-galactose (pH 7.5) to the beads and was incubated overnight at room have shown that HIV-1 particles were internalized by the epithe- temperature for at least 18 h. The eluate was absorbed with 100 ␮lof lium after contact of HIV-1-infected cells with the apical surface protein G-Sepharose B beads to remove residual contaminating IgG. Less than 0.1% of IgG was present in the samples after adsorption. The purity of an epithelial cell line. The virus crossed the epithelial tight was further confirmed using PAGE and Western blot analyses (19), and barrier without infecting the epithelium itself, using transcytosis. IgA-depleted fractions contained no HIV-1-neutralizing activity (see Foot- The transcytosed particles could subsequently infect host submu- note 5). An ELISA was used for quantification of purified IgA (20), and cosal mononucleated target cells, indicating a new mechanism for IgA purified from pooled normal human colostrum (Sigma, Life Technol- ogies, Paisley, U.K.) was used as standard to perform the quantification. virus spread in vivo. Furthermore, this transcellular pathway was blocked by anti-HIV envelope protein dIgA or pIgM purified from Transcytosis assay HIV-1-infected individuals (15). We now show that IgA from To measure transcytosis, the cDNA pIgR-transfected human intestinal ep- HEPS individuals is also able to block transcytosis of HIV-1 pri- ithelial cell line CaCo-2 was used (21). The cell cultures were performed mary isolates across a model of the tight epithelial barrier, sug- on Transwell nitrocellulose filters (0.4-␮m pore size filter, Costar, Cam- gesting a novel mechanism by which these individuals may be bridge, MA) in MEM containing 10% inactivated FCS (Life Technologies) protected against mucosal acquisition of HIV-1. during 8–10 days, until the cell lines formed tight monolayer cultures. One milliliter of medium per well was exchanged at the basolateral side, and 0.5 ml/well was exchanged at the apical side every 72 h.
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