Differential effects on human immunodeficiency virus type 1 replication by alpha-defensins with comparable bactericidal activities.
In addition to their antibacterial activities, certain antimicrobial peptides inactivate enveloped viruses, including the human immunodeficiency virus (HIV). To determine whether peptide bactericidal activities are predictive of antiviral activity, the anti-HIV properties of recombinant human alpha-defensin 5, mouse alpha-defensins, cryptdins (Crp) 3 and 4, and rhesus macaque myeloid alpha-defensins (RMADs) 3 and 4 were determined in vitro. The peptides, purified to homogeneity, had equivalent bactericidal activities that were similar to those of the native molecules. Nuclear magnetic resonance spectroscopy showed RMAD-4 and Crp3 had characteristic alpha-defensin tridisulfide arrays. Of the peptides analyzed, only RMAD-4 inhibited HIV infectivity at 150 microg/ml, and Crp3 unexpectedly increased HIV replication. Quantitative real-time PCRs for minus-strand strong stop DNA and complete viral cDNA synthesis were used to distinguish between preentry and postentry anti-HIV effects by RMAD-4. Viral exposure to RMAD-4 for 1 h prior to infection reduced HIV minus-strand strong stop DNA and HIV cDNA by 4- to 20-fold during the first round of replication, showing that RMAD-4-exposed virions were not entering cells during the first 24 h. On the other hand, when RMAD-4 was added coincident with HIV inoculation, no anti-HIV activity was detected. Viral exposure to Crp3 resulted in a threefold increase in both HIV minus-strand strong stop DNA and HIV cDNA over the first round of replication. Therefore, two alpha-defensins, RMAD-4 and Crp3, inhibit or augment HIV replication, respectively, by mechanisms that precede reverse transcription.
Department of Pathology, D440 Med Sci I, University of California, Irvine, CA 92697-4800, USA.
Hiroki
H
Tanabe
Andre J
AJ
Ouellette
Melanie J
MJ
Cocco
W Edward
WE
Robinson
D000595:Amino Acid Sequence; D051743:CCAAT-Enhancer-Binding Protein-delta; D022762:CCAAT-Enhancer-Binding Proteins / Q000494:pharmacology; D002460:Cell Line; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D011994:Recombinant Proteins / Q000494:pharmacology; D014157:Transcription Factors / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects*; D023084:alpha-Defensins / Q000494:pharmacology*
D022762:CCAAT-Enhancer-Binding Proteins; C497252:CEBPD protein, human; D011994:Recombinant Proteins; D014157:Transcription Factors; D023084:alpha-Defensins; D051743:CCAAT-Enhancer-Binding Protein-delta