Histatin 5-derived peptide with improved fungicidal properties enhances human immunodeficiency virus type 1 replication by promoting viral entry.
Antimicrobial peptides are found in a number of body compartments and are secreted at mucosal surfaces, where they form part of the innate immune system. Many of these small peptides have a broad spectrum of inhibitory activity against bacteria, fungi, parasites, and viruses. Generally, the peptide's mode of action is binding and disruption of membranes due to its amphipathic properties. Histatin 5 is a salivary peptide that inhibits Candida albicans, an opportunistic fungus that causes oropharyngeal candidiasis in a majority of human immunodeficiency virus type 1 (HIV-1)-infected patients progressing towards AIDS. Previously, we increased the fungicidal properties of histatin 5 by replacing amino acids in the active domain of histatin 5 (Dh-5) (A. L. Ruissen, J. Groenink, E. J. Helmerhorst, E. Walgreen-Weterings, W. van't Hof, E. C. Veerman, and A. V. Nieuw Amerongen, Biochem. J. 356:361-368, 2001). In the current study, we tested the anti-HIV-1 activity of Dh-5 and its derivatives. Although Dh-5 inhibited HIV-1 replication, none of the peptide variants were more effective in this respect. In contrast, one of the derivatives, Dhvar2, significantly increased HIV-1 replication by promoting the envelope-mediated cell entry process. Most likely, Dhvar2 affects membranes, thereby facilitating fusion of viral and cellular membranes. This study shows that modification of antimicrobial peptides in order to improve their activity against a pathogen may have unpredictable and unwanted side effects on other pathogens.
Groot
Fedde
F
Department of Human Retrovirology, Academic Medical Center, Meibergdreef 15, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.
Sanders
Rogier W
RW
ter Brake
Olivier
O
Nazmi
Kamran
K
Veerman
Enno C I
EC
Bolscher
Jan G M
JG
Berkhout
Ben
B
D000595:Amino Acid Sequence; D000935:Antifungal Agents / Q000737:chemistry / Q000494:pharmacology*; D002176:Candida albicans / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D015686:Gene Products, env / Q000378:metabolism; D015497:HIV-1 / Q000378:metabolism*; D054808:Histatins; D006801:Humans; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry; D010455:Peptides / Q000737:chemistry*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D012471:Salivary Proteins and Peptides / Q000737:chemistry*; D014779:Virus Replication
D000935:Antifungal Agents; D015686:Gene Products, env; C068075:HTN3 protein, human; D054808:Histatins; D010446:Peptide Fragments; D010455:Peptides; D012471:Salivary Proteins and Peptides