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NONO, “The Red Flag System” That Detects HIV

04 Oct 2018 | By INSERM (Newsroom) | Immunology, inflammation, infectiology and microbiology

Illustration du virus HIV ©Adobestock

There is not one but several types of HIV. Although HIV-1, which is the most common, wreaks havoc in infected populations, this is not the case for HIV-2 which less frequently leads to the development of AIDS. But why does the immune system do a better job of fighting this version of the virus? Researchers from Inserm and Institut Curie looked at this question. Researchers from Inserm and Institut Curie identified the NONO protein, a detector which is more sensitive to HIV-2 and responsible for direct recognition of the virus by the immune system. This work, published in the journal Cell, provides a better understanding of the natural control of HIV and paves the way for new progress in the search for a vaccine for this virus.

AIDS develops when the immune system of an HIV-positive individual becomes unable to fight infection and becomes dramatically weak. The majority of people infected and not treated develop fatal AIDS. But in some cases AIDS does not develop in certain untreated HIV-positive individuals. This explains the existence of several forms of HIV.

Although HIV-1, which affects 25 million people, without treatment leads to AIDS in 99% of cases, this is not the case for HIV-2. This particular form of HIV is very close to HIV-1 but differs in terms of genetics. It is found mostly in West Africa and affects 1 million people. HIV-2 leads to the development of AIDS in fewer than 25% of cases, has no impact on the life expectancy of most people infected, and proves to be difficult to transmit to others. Furthermore, HIV-positive individuals with the HIV-2 form of the virus, and who also contract HIV-1, show improved resistance to the latter.

Researchers from Inserm and Institut Curie in Unit 932 Immunity and Cancer (Inserm/Institut Curie/PSL University/Paris Descartes University) studied the reasons for the immune system’s better control of HIV-2.

In 2010, this research team had already shown that dendritic cells – the immune system’s “sentinel” cells – were able to detect HIV-2 much more efficiently than HIV-1. In order for the immune response to be effective, there needs to be good immune recognition.

Based on this observation, the researchers sought to understand the molecular mechanisms involved in the dendritic cells’ recognition of HIV-2, and to find out why this recognition is effective in comparison to that of HIV-1.

They thus discovered that the NONO protein, located in the dendritic cells, acted as a detector able to recognize the internal casing (or capsid) of HIV-2 a lot better than that of HIV-1, and as a result to trigger an immune response to fight the virus.

The capsid – which surrounds the genetic material of viruses – is made up of proteins, and NONO is apparently able to recognize a specific protein pattern of the capsid of HIV-2.

This study provides a better understanding of the natural mechanisms involved in infection control by HIV. According to Nicolas Manel, Inserm researcher in charge of the study: “the next step in this research project is to understand how this detection system works at the molecular level and how this detection triggers the immune response. We are developing innovative vaccine strategies in the lab, and this discovery paves the way for the new studies needed to develop a new generation of vaccines capable of “imitating” the HIV-2 capsid, and as a result triggering an immune response in people infected with the HIV-1 virus.”

Researcher Contact
Nicolas Manel Chercheur Inserm Responsable de l’équipe « Immunité innée chez l’Homme » Unité 932 Immunité et Cancer +33 (0)1 56 24 64 33 rf.eiruc@lenam.salocin
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  NONO Detects the Nuclear HIV Capsid to Promote cGAS-Mediated Innate Immune Activation   Xavier Lahaye1 Matteo Gentili1 Aymeric Silvin1 Cécile Conrad,1 Léa Picard2,3 Mabel Jouve1 Elina Zueva1 Mathieu Maurin1 Francesca Nadalin1 Gavin J. Knott4 Baoyu Zhao5 Fenglei Du,5 Marlène Rio6,7 Jeanne Amiel6,7 Archa H. Fox4,8,9 Pingwei Li5 Lucie Etienne2 Charles S. Bond4 Laurence Colleaux6,7 and Nicolas Manel1,10   1 Immunity and Cancer Department, Institut Curie, PSL Research University, INSERM U932, 75005 Paris, France 2 CIRI - International Center for Infectiology Research, Inserm U1111, CNRS UMR5308, Ecole Normale Supérieure de Lyon, Université Claude Bernard Lyon 1, Univ Lyon, 69007, Lyon, France 3 LBBE - Laboratoire de Biométrie et Biologie Evolutive CNRS UMR 5558, Universite Lyon 1, Univ Lyon, 69622, Villeurbanne, France 4 School of Molecular Sciences, The University of Western Australia, Crawley, Western Australia 6009, Australia 5 Department of Biochemistry and Biophysics, Texas A&M University, College Station, Texas 77843, USA 6 INSERM UMR 1163, Paris-Descartes-Sorbonne Paris Cité University, Institut IMAGINE, Necker-Enfants Malades Hospital, 75015 Paris, France 7 Service de Génétique, Hôpital Necker-Enfants Malades, AP-HP, Paris, France 8 School of Human Sciences, The University of Western Australia, Crawley, Western Australia 6009, Australia 9 The Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands, Western Australia 6009, Australia 10 Lead contact   Cell.