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* Department of Medicine, Division of Infectious Diseases, Mount Sinai School of Medicine, New York, NY 10029;
Veterans Affairs Medical Center and Department of Laboratory Medicine, University of California, San Francisco, CA 94121;
Institute of Human Virology and Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD 21201; and
Department of Biological Sciences, California State University, Los Angeles, CA 90032
Sexually transmitted infections (STIs) increase the likelihood of HIV transmission. Defensins are part of the innate mucosal immune response to STIs and therefore we investigated their role in HIV infection. We found that human defensins 5 and 6 (HD5 and HD6) promoted HIV infection, and this effect was primarily during viral entry. Enhancement was seen with primary viral isolates in primary CD4+ T cells and the effect was more pronounced with R5 virus compared with X4 virus. HD5 and HD6 promoted HIV reporter viruses pseudotyped with vesicular stomatitis virus and murine leukemia virus envelopes, indicating that defensin-mediated enhancement was not dependent on CD4 and coreceptors. Enhancement of HIV by HD5 and HD6 was influenced by the structure of the peptides, as loss of the intramolecular cysteine bonds was associated with loss of the HIV-enhancing effect. Pro-HD5, the precursor and intracellular form of HD5, also exhibited HIV-enhancing effect. Using a cervicovaginal tissue culture system, we found that expression of HD5 and HD6 was induced in response to Neisseria gonorrhoeae (GC, for gonococcus) infection and that conditioned medium from GC-exposed cervicovaginal epithelial cells with elevated levels of HD5 also enhanced HIV infection. Introduction of small interfering RNAs for HD5 or HD6 abolished the HIV-enhancing effect mediated by GC. Thus, the induction of these defensins in the mucosa in the setting of GC infection could facilitate HIV infection. Furthermore, this study demonstrates the complexity of defensins as innate immune mediators in HIV transmission and warrants further investigation of the mechanism by which defensins modulate HIV infection.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health Grants AI062430, AI073205 (to T.L.C.), AI061482 (to W.L.), and AI063927 (to G.A.J.). E.P. was in part supported by National Institutes of Health Grant 1P20 MD001824.
2 Address correspondence and reprint requests to Dr. Theresa L. Chang, Department of Medicine, Division of Infectious Diseases, Box 1090, One Gustave L. Levy Place, New York, NY, 10029. E-mail address: Theresa.chang{at}mssm.edu
3 Abbreviations used in this paper: STI, sexually transmitted infection; Abu, 
-aminobutyric acid; GC, gonococcus/gonococcal; HBD, human β-defensin; HNP, human neutrophil peptide; LOS, lipooligosaccharide; LTR, long terminal repeat; MOI, multiplicity of infection; MTS, 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium inner salt; Opa, opacity-associated (protein); siRNA, small interfering RNA; VSV, vesicular stomatitis virus.
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