Cyclic and Acyclic Defensins Inhibit Human Immunodeficiency Virus Type-1 Replication by Different Mechanisms

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.

Antibacterial Activity of Four Human Beta-Defensins: HBD-19, HBD-23, HBD-27, and HBD-29

“…The human β-defensins studied here may also have other roles in immune defense including antiviral activity like HBD-2 and HBD-3 [4,31,32]. Moreover, multiple studies have reported that β-defensins recruit monocytes, T-cells, immature dendritic cells and activated neutrophils by acting as chemokines that interact with the chemokine receptors CCR2 and CCR6 [15][16][17][18]33].…”

“…Defensins constitute one of the first lines of innate immune defense against an array of bacteria, fungi, and viruses [1][2][3][4][5]. Many studies have demonstrated that human β-defensins, such as HBD-1, HBD-2, HBD-3, and HBD-4 are antimicrobial peptides expressed by epithelial cells initially as longer precursors [6][7][8][9][10].…”

Antimicrobial and antiviral effects of human defensins: pathogenetic value and prospective application to medicinal therapy

“…Однако в двух работах продемонстрировано от-сутствие зависимости противовирусной активности от линейной формы дефенсинов [173,179]. Следу-ет отметить, что имеющееся к настоящему времени ограниченное число работ, в которых изучали связь конформационной структуры β-дефенсинов с их противовирусной активностью, не позволяет сде-лать однозначный вывод о различиях по этому при-знаку α-и β-дефенсинов.…”

“…Эти же исследователи показали, что дефенсины HBD-1 и HBD-2 не модулируют поверхностный рецептор CD4+ и корецептор ВИЧ, в то время как другие уче-ные [179] продемонстрировали участие дефенсинов HBD-2 и HBD-3 в регуляции экспрессии поверхност-ного рецептора CXCR-4, но не CCR-5 мононуклеаров периферической крови в отсутствие сыворотки. Сан и др.…”

Biological Activities of Natural and Engineered Cyclotides, a Novel Molecular Scaffold for Peptide-Based Therapeutics

“…In animals, the only known circular peptides are θ-defensins, which are expressed in blood leukocytes and bone marrow of Old World monkeys [4,5]. θ-Defensins are antimicrobial peptides with broad-spectrum activities against bacteria, fungi, and viruses [6][7][8]. Backbone cyclized peptides have been also found in plants [9].…”