HIV: entry keys discovered in the cell nucleus
Nicolas Manel est chef de l’équipe Immunité innée chez l'Homme dans l’unité Immunité et cancer (Institut Curie/Inserm U932)
Infection of the body by the human immunodeficiency virus (HIV) leads to regular destruction of certain cells in the immune system: CD4 lymphocytes, commonly called white cells, that protect us against attack from the outside.
To successfully complete its mission of destruction, HIV needs to infect these cells, replicate and multiply. "This ability of HIV to reproduce depends on its ability to penetrate the nucleus of the infected cells and insert itself into the DNA of the host cell", explains Nicolas Manel, Inserm director of research.
The previous steps - from entry of the virus into the CD4 lymphocytes to its anchoring in the envelope of the nucleus via synthesis of viral RNA to DNA - have already been relative well described. However, the mechanisms enabling this DNA to enter the nucleus are poorly understood. "We know that Cyclophiline A (CypA) helps in this HIV infection stage", says Xavier Lahaye, post-doctoral student in the team that conducted the study. "This molecule is linked to the viral capsid, helping the virus to pass through the nucleus envelope." What happens next was still a mystery.
It started with the identification of various mutants of HIV (HIV-1, HIV-2 and simian HIV) for which penetration into the nucleus is blocked by Cyclophiline A. From there, the Human Innate Immunity (Inserm/Institut Curie) team just racked up the discoveries. The SUN2 membrane protein actively participates in blocking HIV mutants from entering the nucleus. SUN2 also appears essential in the infection of dendritic cells and lymphocytes by wild HIV-1 and HIV-2 viruses. This mechanism, which is the same for the various forms of HIV is a weak point in the viral cycle. By understanding better how HIV gets round the defence systems, new strategies for fighting this infection can be discovered. To date, there is no treatment that can completely eliminate HIV. Available therapies act by blocking its multiplication. Replication and multiplication of HIV-1 depends entirely on its access to the target cell nucleus. Any fault identified can be used by the virus, a master in dodging the immune response.
In general, these discoveries are furthering our understanding of the immune system and how it works.
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Xavier Lahaye, Takeshi Satoh, Matteo Gentili, Silvia Cerboni, Aymeric Silvin, Cécile Conrad, Abdelhakim Ahmed-Belkacem, Elisa C. Rodriguez, Jean-François Guichou, Nathalie Bosquet, Matthieu Piel, Roger Le Grand, Megan C. King, Jean-Michel Pawlotsky, Nicolas Manel
Cell report, avril 2016, DOI: http://dx.doi.org/10.1016/j.celrep.2016.03.074