Submitted May 19, 2006
Accepted November 14, 2006
-defensins block the early steps of HIV-1 infection: interference with the binding of gp120 to CD4
Lucinda Furci, Francesca Sironi, Monica Tolazzi, Lia Vassena, and Paolo Lusso*
Unit of Human Virology, DIBIT-San Raffaele Scientific Institute, Milan, Italy
Department of Medical Sciences, University of Cagliari Medical School, Cagliari, Italy
* Corresponding author; email: paolo.lusso{at}hsr.it.
Alpha-defensins are antibiotic peptides that act as natural inhibitors of HIV-1 infection. However, the mechanisms of such inhibition are still unclear. Here we demonstrate that 
-defensins block the earliest steps in the viral infectious cycle, as documented using an HIV-1 envelope-mediated cell fusion assay. A broad-spectrum inhibitory activity was observed on primary and laboratory-adapted HIV-1 isolates irrespective of their coreceptor specificities and genetic subtypes. A primary mechanism of such inhibition was identified as the ability of -defensins to bind specifically both to the primary HIV-1 cellular receptor, CD4, and to the viral envelope glycoprotein, gp120. Moreover, treatment of CD4+ T cells with -defensins caused a dramatic downmodulation of CD4 expression. By monoclonal antibody competition, the regions of interaction with -defensins were mapped to the D1 domain of CD4, and to a surface contiguous to the CD4- and coreceptor-binding sites of gp120. Consistent with these findings, -defensins inhibited the binding of gp120 to CD4. These data demonstrate that -defensins specifically block the initial phase of the HIV infectious cycle, and modulate the expression of CD4, a critical receptor in the physiology of T-cell activation.
