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a-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 a-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 a-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 a-defensins caused a dramatic downmodulation of CD4 expression. By monoclonal antibody competition, the regions of interaction with a-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, a-defensins inhibited the binding of gp120 to CD4. These data demonstrate that a-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.