Abstract
Defensins are antimicrobial peptides expressed by plants and animals. In mammals there are three subfamilies of defensins, distinguished by structural features: α, β and θ. Alpha and β-defensins are linear peptides with broad anti-microbial activity that are expressed by many mammals including humans. In contrast, θ-defensins are cyclic anti-microbial peptides made by several non-human primates but not humans. All three defensin types have anti-HIV-1 activity, but their mechanisms of action differ. We studied the anti-HIV-1 activity of one defensin from each group, HNP-1 (α), HBD-2 (β) and RTD-1 (θ). We examined how each defensin affected HIV-1 infection and demonstrated that the cyclic defensin RTD-1 inhibited HIV-1 entry, while acyclic HNP-1 and HBD-2 inhibited HIV-1 replication even when added 12 hours post-infection and blocked viral replication after HIV-1 cDNA formation. We further found that all three defensins downmodulated CXCR4. Moreover, RTD-1 inactivated X4 HIV-1, while HNP-1 and HBD-2 inactivated both X4 and R5 HIV-1. The data presented here show that acyclic and cyclic defensins block HIV-1 replication by shared and diverse mechanisms. Moreover, we found that HNP-1 and RTD-1 directly inhibited firefly luciferase enzymatic activity, which may affect the interpretation of previously published data.
Highlights
IntroductionAntifungal and antiviral activity have been discovered and classified in various organisms from plants to humans [1,2,3]
Small peptides with antimicrobial, antifungal and antiviral activity have been discovered and classified in various organisms from plants to humans [1,2,3]
The concentration of HNP-1 in plasma has been reported to be at least an order of magnitude lower than the IC50 against HIV-1 that we determined, so HNP-1 is unlikely to be effective against HIV-1 in plasma [42]
Summary
Antifungal and antiviral activity have been discovered and classified in various organisms from plants to humans [1,2,3]. In humans these peptides are termed defensins. Humans have six a-defensins termed human neutrophil proteins 1 through 4 (HNP 1–4) and human defensins 5 and 6 (HD 5 & 6). No human h-defensins have been isolated to date, but humans have three h-defensin pseudogenes that contain premature stop codons. In non-human primates, hdefensins have been isolated from neutrophils and from bone marrow [7,8]. Synthetic h-defensins based on the human pseudogenes have been made in vitro and named retrocyclins [9,10]
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.