15 April 2016 - PRESS RELEASE
Why the immune system fails to fight HIV
An international research group has identified a cellular factor of the human cell that is indispensable to the replication of Human Immunodeficiency Virus (HIV-1). Scientists of the Paul-Ehrlich-Institut at Langen essentially participated.
Why is the immune system unable to combat HIV? Of the cells, HIV chooses human immune system cells as its host. Once integrated into the host genome of these immune cells, the virus´s genes become insusceptible to attack. As soon as treatment is omitted, the virus´s genetic material is reactivated, and the body gets flooded with viruses once again. 1.5 million people die every year from the consequences of HIV infection: the immune deficiency syndrome AIDS. Dr Renate König, head of the research group "Cellular Aspects of Pathogen Host Interactions" of the Paul-Ehrlich Institut and scientist in the DZIF, has been studying the phenomenon for a long time, asking why the human immune system fails to fight HIV-1.
The researchers have now reached one important milestone toward achieving this goal in an international research collaboration. They have identified NLRX1 (nucleotide-binding oligomerization domain, leucine rich repeat containing X1) as an important factor. This protein 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<acronym title="Human Immunodeficiency Virus"></acronym>-1 replication. The fact that it does play a central role, and which mechanisms it uses, has so far been unknown.
The research team was able to show that NLRX1 attenuates the innate immune system by binding STING, an important factor in combating viruses by stimulating the immune system. These defence 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 cytonkine respnse was considerably increased, thus inhibiting import of the virus DNA into the nucleus.
Therefore, NLRX1 could be an attractive target structure for the development of therapies for the treatment of HIV-1. Active blockers against NLRX1 should enhance the innate immune response to HIV-1.
Guo H, König R, Deng M, Riess M, Mo J, Zhang L, Petrucelli A, Yoh SM, Barefood B, Samo 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 19: 515-528.