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PLoS One. 2015 Mar 20;10(3):e0122020. doi: 10.1371/journal.pone.0122020. eCollection 2015.

Colorectal mucus binds DC-SIGN and inhibits HIV-1 trans-infection of CD4+ T-lymphocytes.

Author information

1
Laboratory of Experimental Virology, Department of Medical Microbiology, Centre for Infection and Immunity, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
2
Laboratory of Experimental Virology, Department of Medical Microbiology, Centre for Infection and Immunity, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, United States of America.
3
Department of Dermatology, Medical Centre of the University of Amsterdam, Amsterdam, The Netherlands; STI outpatient clinic, Cluster Infectious Diseases, Public Health Service Amsterdam and Centre for Infections and Immunity Amsterdam, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
4
Mass Spectrometry of Biomacromolecules, Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, the Netherlands.
5
Division of Infectious Diseases, Faculty of Medicine, Imperial College, London, United Kingdom.
6
Department of Medical Biochemistry, Medical Centre of the University of Amsterdam, Amsterdam, the Netherlands.
7
Laboratory of Experimental Virology, Department of Medical Microbiology, Centre for Infection and Immunity, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; Department of Clinical Infection, Microbiology and Immunology, Institute of Infection and Global Health, University of Liverpool, Liverpool, United Kingdom.

Abstract

Bodily secretions, including breast milk and semen, contain factors that modulate HIV-1 infection. Since anal intercourse caries one of the highest risks for HIV-1 transmission, our aim was to determine whether colorectal mucus (CM) also contains factors interfering with HIV-1 infection and replication. CM from a number of individuals was collected and tested for the capacity to bind DC-SIGN and inhibit HIV-1 cis- or trans-infection of CD4+ T-lymphocytes. To this end, a DC-SIGN binding ELISA, a gp140 trimer competition ELISA and HIV-1 capture/ transfer assays were utilized. Subsequently we aimed to identify the DC-SIGN binding component through biochemical characterization and mass spectrometry analysis. CM was shown to bind DC-SIGN and competes with HIV-1 gp140 trimer for binding. Pre-incubation of Raji-DC-SIGN cells or immature dendritic cells (iDCs) with CM potently inhibits DC-SIGN mediated trans-infection of CD4+ T-lymphocytes with CCR5 and CXCR4 using HIV-1 strains, while no effect on direct infection is observed. Preliminary biochemical characterization demonstrates that the component seems to be large (>100kDa), heat and proteinase K resistant, binds in a α1-3 mannose independent manner and is highly variant between individuals. Immunoprecipitation using DC-SIGN-Fc coated agarose beads followed by mass spectrometry indicated lactoferrin (fragments) and its receptor (intelectin-1) as candidates. Using ELISA we showed that lactoferrin levels within CM correlate with DC-SIGN binding capacity. In conclusion, CM can bind the C-type lectin DC-SIGN and block HIV-1 trans-infection of both CCR5 and CXCR4 using HIV-1 strains. Furthermore, our data indicate that lactoferrin is a DC-SIGN binding component of CM. These results indicate that CM has the potential to interfere with pathogen transmission and modulate immune responses at the colorectal mucosa.

PMID:
25793526
PMCID:
PMC4368515
DOI:
10.1371/journal.pone.0122020
[Indexed for MEDLINE]
Free PMC Article

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