Abstract
The repeat region of DC-SIGNR (CD209L) is polymorphic on the genomic level, and, in a separate study, we observed a correlation between the DC-SIGNR genotype and HIV-1 susceptibility during sexual contact. However, previous investigations using immunohistochemistry failed to detect membrane-bound DC-SIGNR on cells in the genital and rectal mucosa. We therefore explored the presence of DC-SIGNR in these compartments with a more sensitive limiting dilution RT-PCR, which also allowed for quantification of alternatively spliced mRNA isoforms. DC-SIGN (CD209) and DC-SIGNR mRNA transcript isoforms were found in all 12 vaginal and two rectal biopsies obtained from 14 healthy individuals. For DC-SIGNR, we detected significantly more isoform than full-length transcripts (mean copy numbers/μg RNA: 602 vs 26; P=0.0009). Four mucosal samples lacked full-length DC-SIGNR transcripts entirely. Cloning and sequencing of DC-SIGNR mRNA in three additional individuals revealed a diverse repertoire of DC-SIGNR isoforms, many of which encoded for proteins predicted to be soluble and secreted. Indeed, in one vaginal sample, we detected only soluble isoforms. In conjunction with our prior observation that the DC-SIGNR genotype has an effect on HIV-1 transmission in vivo, these findings emphasize that DC-SIGNR, in addition to DC-SIGN, should be considered as a cofactor in sexual HIV-1 transmission. Soluble isoforms, in particular, may modulate the efficiency of viral transmission and dissemination.
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Acknowledgements
We thank EJ Soilleux for her suggestions concerning amplification of DC-SIGNR mRNA from DCs and her kind gift of DC-SIGNR cDNA, A Desbien for cell culture, C Wang for statistics, G Gao for helpful comments, H Zhu, Y Hwangbo, and LM Hampson for technical assistance, PJ Nelson for patient recruitment, and M Bull for editing the manuscript. This work was supported by the National Institutes of Health Grants AI 45402 (TZ), AI 49109 (TZ), AI 56994 (TZ), AI 27757 (The University of Washington CFAR Clinical Research Core Award to HL, New Investigator Award to FH), AI 51980 (FH), AI 41535 (LC), AI 35605 (MJM), and a Burroughs Wellcome Clinical Scientist Award (MJM).
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Liu, H., Hladik, F., Andrus, T. et al. Most DC-SIGNR transcripts at mucosal HIV transmission sites are alternatively spliced isoforms. Eur J Hum Genet 13, 707–715 (2005). https://doi.org/10.1038/sj.ejhg.5201409
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DOI: https://doi.org/10.1038/sj.ejhg.5201409
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