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.
Highlights
Despite recent advances in the understanding of HIV-1 infection, major scientific mysteries remain and HIV-1 infection is still a global challenge for mankind
To investigate the consequences of protein modification by the myeloperoxidase/hypochlorous acid (HOCl) immune defence system pooled plasma proteins were isolated from human plasma, modified by HOCl to generate Immune defence-altered pooled plasma proteins (Idea-PP) and subsequently tested for their capacity to bind to HIV-1 gp120, its receptor CD4 and to the protein disulfide isomerase (PDI)
surface plasmon resonance (SPR) demonstrated that immobilized gp120, CD4 as well as PDI bind Idea-PP with very high affinity (Fig. 1D, E, F)
Summary
Despite recent advances in the understanding of HIV-1 infection, major scientific mysteries remain and HIV-1 infection is still a global challenge for mankind. Genome entry into the target cell involves for the enveloped HIV-1 several major steps. In most infections HIV-1 binds to a cell-surface receptor and co-receptors; subsequently, as binding is not sufficient for entry, the HIV-1 and the host cell membrane fuse. Membrane fusogenicity is the result of an active virus-host cell interaction process that induces conformational changes within the viral envelope protein [1]. The chemokine receptor CCR5 is the co-receptor utilized by macrophage- or Mtropic viruses. They are referred to as R5 viruses [2]. The chemokine receptor CXCR4 is the co-receptor for T-tropic or X4 viruses [3] It is especially used by viruses appearing later in HIV-1 infection [4]. Dual-tropic HIV-1 strains use both co-receptors (R5X4 strains)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: 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.
