Alpha-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 alpha-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 alpha-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 alpha-defensins caused a dramatic downmodulation of CD4 expression. By monoclonal antibody competition, the regions of interaction with alpha-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, alpha-defensins inhibited the binding of gp120 to CD4. These data demonstrate that alpha-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.
Furci
Lucinda
L
Unit of Human Virology, Department of Biological and Technological Research (DIBIT), San Raffaele Scientific Institute, Milan, Italy.
Sironi
Francesca
F
Tolazzi
Monica
M
Vassena
Lia
L
Lusso
Paolo
P
D001665:Binding Sites; D015704:CD4 Antigens / Q000378:metabolism*; D015699:HIV Envelope Protein gp120 / Q000378:metabolism*; D015658:HIV Infections / Q000276:immunology / Q000517:prevention & control* / Q000821:virology; D015497:HIV-1 / Q000187:drug effects / Q000472:pathogenicity / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D011485:Protein Binding / Q000187:drug effects; D011994:Recombinant Proteins / Q000494:pharmacology; D053586:Virus Internalization / Q000187:drug effects; D023084:alpha-Defensins / Q000276:immunology / Q000494:pharmacology*
D015704:CD4 Antigens; D015699:HIV Envelope Protein gp120; D011994:Recombinant Proteins; D023084:alpha-Defensins; C406413:human neutrophil peptide 1; C406416:human neutrophil peptide 2