Neutrophils Turn Plasma Proteins into Weapons against HIV-1

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.

N-chlorination mediates protective and immunomodulatory effects of oxidized human plasma proteins

“…In this study, we describe HOCl-modified HSA as a novel pro-inflammatory mediator, which can promote cell survival by binding to highly immunogenic foreign antigens and reducing their phagocytosis at sites of bacterial infection. A similar phenomenon was observed in other studies, where HOCl-modified HSA was shown to bind and neutralize proteins from HIV and West Nile virus (Vossmann et al, 2008; Speth et al, 2013).…”

Panton-Valentine Leukocidin associated with S. aureus osteomyelitis activates platelets via neutrophil secretion products

“…In addition to HNPs, PVL-stimulated neutrophils also secreted substantial amounts of myeloperoxidase. The myeloperoxidase product HOCl reacts with protein moieties and lipids, generating HOCl-modified-albumin, LDL and other species that can potently activate platelets 31 , 32 . HOCl also leads to the production of the α, β- unsaturated aldehyde acrolein 21 .…”

Activation of RidA chaperone function by N-chlorination

“…Interestingly, this inhibition depends on N -chlorination of lysine residues and is irreversible. Moreover, HOCl-modified human serum albumin was shown to bind and inhibit proteins from West Nile virus and HIV 50 51 . These findings suggest a critical role of HOCl-modified plasma proteins during infection and inflammatory processes.…”