Neutrophils Turn Plasma Proteins into Weapons against HIV-1

PLoS One. 2013 Jun 26;8(6):e66073. doi: 10.1371/journal.pone.0066073. Print 2013.

Abstract

As a consequence of innate immune activation granulocytes and macrophages produce hypochlorite/hypochlorous acid (HOCl) via secretion of myeloperoxidase (MPO) to the outside of the cells, where HOCl immediately reacts with proteins. Most proteins that become altered by this system do not belong to the invading microorganism but to the host. While there is no doubt that the myeloperoxidase system is capable of directly inactivating HIV-1, we hypothesized that it may have an additional indirect mode of action. We show in this article that HOCl is able to chemically alter proteins and thus turn them into Idea-Ps (Idea-P = immune defence-altered protein), potent amyloid-like and SH-groups capturing antiviral weapons against HIV-1. HOCl-altered plasma proteins (Idea-PP) have the capacity to bind efficiently and with high affinity to the HIV-1 envelope protein gp120, and to its receptor CD4 as well as to the protein disulfide isomerase (PDI). Idea-PP was able to inhibit viral infection and replication in a cell culture system as shown by reduced number of infected cells and of syncytia, resulting in reduction of viral capsid protein p24 in the culture supernatant. The unmodified plasma protein fraction had no effect. HOCl-altered isolated proteins antithrombin III and human serum albumin, taken as representative examples of the whole pool of plasma proteins, were both able to exert the same activity of binding to gp120 and inhibition of viral proliferation. These data offer an opportunity to improve the understanding of the intricacies of host-pathogen interactions and allow the generation of the following hypothetical scheme: natural immune defense mechanisms generate by posttranslational modification of plasma proteins a potent virucidal weapon that immobilizes the virus as well as inhibits viral fusion and thus entry into the host cells. Furthermore simulation of this mechanism in vitro might provide an interesting new therapeutic approach against microorganisms.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-HIV Agents / chemistry*
  • Anti-HIV Agents / metabolism
  • Anti-HIV Agents / pharmacology*
  • Blood Proteins / chemistry*
  • Blood Proteins / metabolism
  • Blood Proteins / pharmacology*
  • CD4 Antigens / metabolism
  • HIV Envelope Protein gp120 / metabolism
  • HIV-1 / drug effects*
  • HIV-1 / metabolism
  • HIV-1 / physiology
  • HeLa Cells
  • Host-Pathogen Interactions
  • Humans
  • Hypochlorous Acid / chemistry
  • Models, Molecular
  • Neutrophils / metabolism*
  • Protein Conformation
  • Protein Disulfide-Isomerases / metabolism
  • Sulfhydryl Compounds / chemistry
  • Virus Internalization / drug effects

Substances

  • Anti-HIV Agents
  • Blood Proteins
  • CD4 Antigens
  • HIV Envelope Protein gp120
  • Sulfhydryl Compounds
  • gp120 protein, Human immunodeficiency virus 1
  • Hypochlorous Acid
  • Protein Disulfide-Isomerases

Grant support

The work was supported in parts by grants to B.E.K. from the Deutsche Forschungsgemein-schaft by SFB 293. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.