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Blood, 1 April 2007, Vol. 109, No. 7, pp. 2928-2936.
Prepublished online as a Blood First Edition Paper on November 28, 2006; DOI 10.1182/blood-2006-05-024489.
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IMMUNOBIOLOGY
 -defensins block the early steps of HIV-1 infection: interference with the binding of gp120 to CD4
Lucinda Furci1,
Francesca Sironi1,
Monica Tolazzi1,
Lia Vassena1, and
Paolo Lusso1,2
1 Unit of Human Virology, Department of Biological and Technological Research (DIBIT), San Raffaele Scientific Institute, Milan, Italy;
2 Department of Medical Sciences, University of Cagliari Medical School, Italy
 -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 specificity and genetic subtype. 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.
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