Multifaceted mechanisms of HIV-1 entry inhibition by human α-defensin.
The human neutrophil peptide 1 (HNP-1) is known to block the human immunodeficiency virus type 1 (HIV-1) infection, but the mechanism of inhibition is poorly understood. We examined the effect of HNP-1 on HIV-1 entry and fusion and found that, surprisingly, this α-defensin inhibited multiple steps o...
| Main Authors: | , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
2012
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| _version_ | 1797090249063530496 |
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| author | Demirkhanyan, L Marin, M Padilla-Parra, S Zhan, C Miyauchi, K Jean-Baptiste, M Novitskiy, G Lu, W Melikyan, G |
| author_facet | Demirkhanyan, L Marin, M Padilla-Parra, S Zhan, C Miyauchi, K Jean-Baptiste, M Novitskiy, G Lu, W Melikyan, G |
| author_sort | Demirkhanyan, L |
| collection | OXFORD |
| description | The human neutrophil peptide 1 (HNP-1) is known to block the human immunodeficiency virus type 1 (HIV-1) infection, but the mechanism of inhibition is poorly understood. We examined the effect of HNP-1 on HIV-1 entry and fusion and found that, surprisingly, this α-defensin inhibited multiple steps of virus entry, including: (i) Env binding to CD4 and coreceptors; (ii) refolding of Env into the final 6-helix bundle structure; and (iii) productive HIV-1 uptake but not internalization of endocytic markers. Despite its lectin-like properties, HNP-1 could bind to Env, CD4, and other host proteins in a glycan- and serum-independent manner, whereas the fusion inhibitory activity was greatly attenuated in the presence of human or bovine serum. This demonstrates that binding of α-defensin to molecules involved in HIV-1 fusion is necessary but not sufficient for blocking the virus entry. We therefore propose that oligomeric forms of defensin, which may be disrupted by serum, contribute to the anti-HIV-1 activity perhaps through cross-linking virus and/or host glycoproteins. This notion is supported by the ability of HNP-1 to reduce the mobile fraction of CD4 and coreceptors in the plasma membrane and to precipitate a core subdomain of Env in solution. The ability of HNP-1 to block HIV-1 uptake without interfering with constitutive endocytosis suggests a novel mechanism for broad activity against this and other viruses that enter cells through endocytic pathways. |
| first_indexed | 2024-03-07T03:15:48Z |
| format | Journal article |
| id | oxford-uuid:b5baaa4a-da40-4dd5-b46b-56a488793c71 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T03:15:48Z |
| publishDate | 2012 |
| record_format | dspace |
| spelling | oxford-uuid:b5baaa4a-da40-4dd5-b46b-56a488793c712022-03-27T04:35:48ZMultifaceted mechanisms of HIV-1 entry inhibition by human α-defensin.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:b5baaa4a-da40-4dd5-b46b-56a488793c71EnglishSymplectic Elements at Oxford2012Demirkhanyan, LMarin, MPadilla-Parra, SZhan, CMiyauchi, KJean-Baptiste, MNovitskiy, GLu, WMelikyan, GThe human neutrophil peptide 1 (HNP-1) is known to block the human immunodeficiency virus type 1 (HIV-1) infection, but the mechanism of inhibition is poorly understood. We examined the effect of HNP-1 on HIV-1 entry and fusion and found that, surprisingly, this α-defensin inhibited multiple steps of virus entry, including: (i) Env binding to CD4 and coreceptors; (ii) refolding of Env into the final 6-helix bundle structure; and (iii) productive HIV-1 uptake but not internalization of endocytic markers. Despite its lectin-like properties, HNP-1 could bind to Env, CD4, and other host proteins in a glycan- and serum-independent manner, whereas the fusion inhibitory activity was greatly attenuated in the presence of human or bovine serum. This demonstrates that binding of α-defensin to molecules involved in HIV-1 fusion is necessary but not sufficient for blocking the virus entry. We therefore propose that oligomeric forms of defensin, which may be disrupted by serum, contribute to the anti-HIV-1 activity perhaps through cross-linking virus and/or host glycoproteins. This notion is supported by the ability of HNP-1 to reduce the mobile fraction of CD4 and coreceptors in the plasma membrane and to precipitate a core subdomain of Env in solution. The ability of HNP-1 to block HIV-1 uptake without interfering with constitutive endocytosis suggests a novel mechanism for broad activity against this and other viruses that enter cells through endocytic pathways. |
| spellingShingle | Demirkhanyan, L Marin, M Padilla-Parra, S Zhan, C Miyauchi, K Jean-Baptiste, M Novitskiy, G Lu, W Melikyan, G Multifaceted mechanisms of HIV-1 entry inhibition by human α-defensin. |
| title | Multifaceted mechanisms of HIV-1 entry inhibition by human α-defensin. |
| title_full | Multifaceted mechanisms of HIV-1 entry inhibition by human α-defensin. |
| title_fullStr | Multifaceted mechanisms of HIV-1 entry inhibition by human α-defensin. |
| title_full_unstemmed | Multifaceted mechanisms of HIV-1 entry inhibition by human α-defensin. |
| title_short | Multifaceted mechanisms of HIV-1 entry inhibition by human α-defensin. |
| title_sort | multifaceted mechanisms of hiv 1 entry inhibition by human α defensin |
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