α-Defensins Block the Early Steps of HIV-1 Infection: Interference with the Binding of gp120 to CD4

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 α-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 laboratoryadapted HIV-1 isolates irrespective of their coreceptor specificities and genetic subtypes. A primary mechanism of such inhibition was identified as the ability of α-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 α-defensins caused a dramatic downmodulation of CD4 expression. By monoclonal antibody competition, the regions of interaction with α-defensins were mapped to the D1 domain of CD4, and to a surface contiguous to the CD4and coreceptor-binding sites of gp120. Consistent with these findings, α-defensins inhibited the binding of gp120 to CD4. These data demonstrate that α-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. only. For personal use at PENN STATE UNIVERSITY on February 23, 2013. bloodjournal.hematologylibrary.org From