The theta-defensin, retrocyclin, inhibits HIV-1 entry.

Retrocyclin is a circular antimicrobial 18-residue peptide encoded in the human genome by a theta-defensin pseudogene. In the human genome, the gene for retrocyclin is inactivated by an in-frame stop codon in its signal sequence but its mature coding sequence is intact. The peptide corresponding to the processed human retrocyclin, generated by solid phase peptide synthesis, inhibited replication of R5 and X4 strains of HIV-1 in human cells. Luciferase reporter virus and Vpr-BLaM entry assays were used to demonstrate that retrocyclin specifically blocked R5 and X4 HIV-1 replication at entry. Surface plasmon resonance demonstrated that retrocyclin bound to soluble CD4 and gp120, but gp120 cell-binding assays revealed that retrocyclin did not fully inhibit the binding of soluble CD4 to gp120. A fluorescent retrocyclin congener localized in cell-surface patches either alone or colocalized with CD4, CXCR4, and CCR5. In the aggregate, these results suggest that retrocyclin blocks an entry step in HIV-1 replication. Retrocyclin represents a new class of small molecule HIV-1 entry inhibitors.