Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Why is the immune system unable to combat HIV? Key factor identified

14.04.2016

An international research group with essential participation of the Paul-Ehrlich-Institut, has identified NLRX1, a cellular factor of the human cell that is indispensable to the replication of Human Immunodeficiency Virus (HIV-1). This factor plays a key role in attenuating the innate immune system towards HIV-1. Until now, the significance of NLRX1 for the replication of HIV-1 and the attenuation of the immune system was not known. The novel research finding will lead to new therapeutic approaches. The research results are reported in Cell Host Microbe in its oedition of 13.04.2016

HIV-1 uses human proteins (host proteins) for its own replication and prevents the human immune system from combating it successfully. Dr Renate König, head of the research group “Cellular Aspects of Pathogen Host Interactions” of the Paul-Ehrlich-Institut, and her colleagues have been studying this phenomenon for a long time, asking why the human immune system fails to fight HIV-1.


NLRX1 and HIV-1 infection a) NLRX1 attenuates immune reactions, thus enabling HIV replication. b) If NLRX1 is deactivated, the protective mechanisms can take effect and block HIV replication.

Source: PEI

To identify the underlying reason could help develop both enhancers for future efficacious vaccines and new immune-modulated HIV antivirals. The researchers have now reached one important milestone toward achieving this goal in an international research collaboration with Dr Jenny Ting, University of North Carolina at Chapel Hill, NC, USA, and Dr Sumit Chanda, Sanford-Burnham Prebys Medical Discovery Institute, San Diego, CA.

They have identified NLRX1 (nucleotide-binding oligomerization domain, leucine rich repeat containing X1) as an important factor. This protein belongs to the NOD-like receptor family (NOD-like receptors, NLR) of pattern recognition receptors. It acts as a fine-tuning regulator, which can deactivate the early warning system of the immune system. In a high-throughput procedure, NLRX1 had already been identified by König and colleagues as one out of 295 potential proteins important for HIV-1 replication [1]. The fact that it does play a central role, and which mechanisms it uses, has so far been unknown.

König and her international research partners provided evidence that NLRX1 enables HIV-1 infection in immune cells such as macrophages and dendritic cells (cells of the human immune system). The research team was able to show that NLRX1 attenuates the innate immune system by binding STING (stimulator of interferon genes). STING, an important factor in combating viruses, acts as a mediator. After (virus) DNA has been sensed by the receptor cGAS in the cytoplasm of the cells, STING binds to the factor TBK1 (TANK-binding kinase 1) and activates it.

Subsequently, type-I interferon and pro-inflammatory cytokines are produced. Moreover, the binding of STING to TBK1 leads to the activation of interferon-stimulating genes (ISG), which prevent the insertion of virus DNA into the nucleus of the cell, thus inhibiting its replication. These defense mechanisms are deactivated when NLRX1 binds to STING. By silencing NLRX, the researchers were able to show that this protein does indeed play a key role, because the cytokine response was considerably increased, thus inhibiting import of the virus DNA into the nucleus.

Therefore, NLRX1 is an attractive target structure for the development of therapies for the treatment of HIV-1. Advanced therapeutics, which block NLRX1 could also be used to act as adjuvants enhancing the efficacy of vaccines. “We believe that our research results can speed up the development of such active substances against HIV-1, which contribute to enhancing the innate immune response to HIV-1”, said König, explaining the significance of these research results.

Original Publication

Guo H, König R, Deng M, Riess M, Mo J, Zhang L, Petrucelli A, Yoh SM, Barefood B, Ventevogel M, Sempowski GD, Zhang A, Colberg-Poley AM, Feng H, Lemon SM, Liu Y, Zhang Y, Wen H, Zhang Z, Damania B, Tsao LC, Wang Q, Su L, Duncan JA, Chanda SK, Ting JPY (2016): NLRX1 Sequesters STING to Negatively Regulate the Interferon Response, Thereby Facilitating the Replication of HIV-1 and DNA Viruses.
Cell Host Microbe. Volume 19, Issue 4, p515–528
DOI: http://dx.doi.org/10.1016/j.chom.2016.03.001

[1] König R, Zhou Y, Elleder D, Diamond TL, Bonamy GMC, Irelan JT, Chiang C, Tu BP, De Jesus PD, Lilley CE, Seidel S, Opaluch AM, Caldwell J, Weitzman MD, Kuhen KL, Bandyopadhyay S, Ideker T, Orth A, Miraglia LJ, Bushman FD, Young JA, Chanda SK (2008): Global analysis of host-pathogen interactions that regulate early-stage HIV-1 replication.
Cell 135: 49-60.

The Paul-Ehrlich-Institut, the Federal Institute for Vaccines and Biomedicines, in Langen near Frankfurt/Main is a senior federal authority reporting to the Federal Ministry of Health (Bundesministerium für Gesundheit, BMG). It is responsible for the research, assessment, and marketing authorisation of biomedicines for human use and immunological veterinary medicinal products. Its remit also includes the authorisation of clinical trials and pharmacovigilance, i.e. recording and evaluation of potential adverse effects.

Other duties of the institute include official batch control, scientific advice and inspections. In-house experimental research in the field of biomedicines and life science form an indispensable basis for the manifold tasks performed at the institute.

The Paul-Ehrlich-Institut, with its roughly 800 members of staff, also has advisory functions nationally (federal government, federal states (Länder)), and internationally (World Health Organisation, European Medicines Agency, European Commission, Council of Europe etc.).

Weitere Informationen:

http://www.cell.com/cell-host-microbe/fulltext/S1931-3128(16)30063-4 - Abstract of the publication
http://www.ncbi.nlm.nih.gov/pubmed/18854154 - Abstract of the Cell-Paper, mentioned in the press release
http://www.pei.de/EN/information/journalists-press/press-releases/2016/10-immune... - This press release on the PEI-Website

Dr. Susanne Stöcker | idw - Informationsdienst Wissenschaft

More articles from Life Sciences:

nachricht Scientists uncover the role of a protein in production & survival of myelin-forming cells
19.07.2018 | Advanced Science Research Center, GC/CUNY

nachricht NYSCF researchers develop novel bioengineering technique for personalized bone grafts
18.07.2018 | New York Stem Cell Foundation

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Future electronic components to be printed like newspapers

A new manufacturing technique uses a process similar to newspaper printing to form smoother and more flexible metals for making ultrafast electronic devices.

The low-cost process, developed by Purdue University researchers, combines tools already used in industry for manufacturing metals on a large scale, but uses...

Im Focus: First evidence on the source of extragalactic particles

For the first time ever, scientists have determined the cosmic origin of highest-energy neutrinos. A research group led by IceCube scientist Elisa Resconi, spokesperson of the Collaborative Research Center SFB1258 at the Technical University of Munich (TUM), provides an important piece of evidence that the particles detected by the IceCube neutrino telescope at the South Pole originate from a galaxy four billion light-years away from Earth.

To rule out other origins with certainty, the team led by neutrino physicist Elisa Resconi from the Technical University of Munich and multi-wavelength...

Im Focus: Magnetic vortices: Two independent magnetic skyrmion phases discovered in a single material

For the first time a team of researchers have discovered two different phases of magnetic skyrmions in a single material. Physicists of the Technical Universities of Munich and Dresden and the University of Cologne can now better study and understand the properties of these magnetic structures, which are important for both basic research and applications.

Whirlpools are an everyday experience in a bath tub: When the water is drained a circular vortex is formed. Typically, such whirls are rather stable. Similar...

Im Focus: Breaking the bond: To take part or not?

Physicists working with Roland Wester at the University of Innsbruck have investigated if and how chemical reactions can be influenced by targeted vibrational excitation of the reactants. They were able to demonstrate that excitation with a laser beam does not affect the efficiency of a chemical exchange reaction and that the excited molecular group acts only as a spectator in the reaction.

A frequently used reaction in organic chemistry is nucleophilic substitution. It plays, for example, an important role in in the synthesis of new chemical...

Im Focus: New 2D Spectroscopy Methods

Optical spectroscopy allows investigating the energy structure and dynamic properties of complex quantum systems. Researchers from the University of Würzburg present two new approaches of coherent two-dimensional spectroscopy.

"Put an excitation into the system and observe how it evolves." According to physicist Professor Tobias Brixner, this is the credo of optical spectroscopy....

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Leading experts in Diabetes, Metabolism and Biomedical Engineering discuss Precision Medicine

13.07.2018 | Event News

Conference on Laser Polishing – LaP: Fine Tuning for Surfaces

12.07.2018 | Event News

11th European Wood-based Panel Symposium 2018: Meeting point for the wood-based materials industry

03.07.2018 | Event News

 
Latest News

A smart safe rechargeable zinc ion battery based on sol-gel transition electrolytes

20.07.2018 | Power and Electrical Engineering

Reversing cause and effect is no trouble for quantum computers

20.07.2018 | Information Technology

Princeton-UPenn research team finds physics treasure hidden in a wallpaper pattern

20.07.2018 | Materials Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>