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Multifaceted mechanisms of HIV-1 entry inhibition by human α-defensin.

Abstract
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.
AuthorsLusine H Demirkhanyan, Mariana Marin, Sergi Padilla-Parra, Changyou Zhan, Kosuke Miyauchi, Maikha Jean-Baptiste, Gennadiy Novitskiy, Wuyuan Lu, Gregory B Melikyan
JournalThe Journal of biological chemistry (J Biol Chem) Vol. 287 Issue 34 Pg. 28821-38 (Aug 17 2012) ISSN: 1083-351X [Electronic] United States
PMID22733823 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • CD4 Antigens
  • alpha-Defensins
  • env Gene Products, Human Immunodeficiency Virus
  • human neutrophil peptide 1
Topics
  • Animals
  • CD4 Antigens (genetics, metabolism)
  • Cattle
  • Cell Membrane (genetics, metabolism)
  • Endocytosis
  • HEK293 Cells
  • HIV-1 (physiology)
  • HeLa Cells
  • Humans
  • Protein Binding
  • Protein Multimerization
  • Virus Internalization
  • alpha-Defensins (genetics, metabolism)
  • env Gene Products, Human Immunodeficiency Virus (genetics, metabolism)

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