Human defensins 5 and 6 enhance HIV-1 infectivity through promoting HIV attachment

BACKGROUND: Concurrent sexually transmitted infections (STIs) increase the likelihood of HIV transmission. The levels of defensins are frequently elevated in genital fluids from individuals with STIs. We have previously shown that human defensins 5 and 6 (HD5 and HD6) promote HIV entry and contribute to Neisseria gonorrhoeae-mediated enhancement of HIV infectivity in vitro. In this study, we dissect the molecular mechanism of the HIV enhancing effect of defensins. RESULTS: HD5 and HD6 primarily acted on the virion to promote HIV infection. Both HD5 and HD6 antagonized the anti-HIV activities of inhibitors of HIV entry (TAK 779) and fusion (T-20) when the inhibitors were present only during viral attachment; however, when these inhibitors were added back during viral infection they overrode the HIV enhancing effect of defensins. HD5 and HD6 enhanced HIV infectivity by promoting HIV attachment to target cells. Studies using fluorescent HIV containing Vpr-GFP indicated that these defensins enhanced HIV attachment by concentrating virus particles on the target cells. HD5 and HD6 blocked anti-HIV activities of soluble glycosaminoglycans including heparin, chondroitin sulfate, and dextran sulfate. However, heparin, at a high concentration, diminished the HIV enhancing effect of HD5, but not HD6. Additionally, the degree of the HIV enhancing effect of HD5, but not HD6, was increased in heparinase-treated cells. These results suggest that HD5 and haparin/heparan sulfate compete for binding to HIV. CONCLUSIONS: HD5 and HD6 increased HIV infectivity by concentrating virus on the target cells. These defensins may have a negative effect on the efficacy of microbicides, especially in the setting of STIs.