The Capsids of HIV-1 and HIV-2 Determine Immune Detection of the Viral cDNA by the Innate Sensor cGAS in Dendritic Cells

• Published in: Immunity (Cambridge, Mass.) Vol. 39; no. 6; pp. 1132 - 1142
• Main Authors: Lahaye, Xavier, Satoh, Takeshi, Gentili, Matteo, Cerboni, Silvia, Conrad, Cécile, Hurbain, Ilse, El Marjou, Ahmed, Lacabaratz, Christine, Lelièvre, Jean-Daniel, Manel, Nicolas
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 12.12.2013; Elsevier Limited; Elsevier
• Subjects: Biochemistry, Molecular Biology; Capsid; Capsid - immunology; Cells, Cultured; Dendritic Cells; Dendritic Cells - immunology; Dendritic Cells - virology; DNA, Complementary; DNA, Complementary - metabolism; DNA, Viral; DNA, Viral - metabolism; Experiments; HIV Infections; HIV Infections - immunology; HIV Infections - virology; HIV-1; HIV-1 - genetics; HIV-1 - immunology; HIV-1 - metabolism; HIV-2; HIV-2 - genetics; HIV-2 - immunology; HIV-2 - metabolism; Human immunodeficiency virus 1; Human immunodeficiency virus 2; Humans; Immune system; Immunity, Innate; Immunity, Innate - physiology; Infections; Life Sciences; Lymphocytes; Microscopy; Models, Biological; Nucleotidyltransferases; Nucleotidyltransferases - metabolism; Proteins
• ISSN: 1074-7613; 1097-4180; 1097-4180
• DOI: 10.1016/j.immuni.2013.11.002

HIV-2 is less pathogenic for humans than HIV-1 and might provide partial cross-protection from HIV-1-induced pathology. Although both viruses replicate in the T cells of infected patients, only HIV-2 replicates efficiently in dendritic cells (DCs) and activates innate immune pathways. How HIV is sensed in DC is unknown. Capsid-mutated HIV-2 revealed that sensing by the host requires viral cDNA synthesis, but not nuclear entry or genome integration. The HIV-1 capsid prevented viral cDNA sensing up to integration, allowing the virus to escape innate recognition. In contrast, DCs sensed capsid-mutated HIV-1 and enhanced stimulation of T cells in the absence of productive infection. Finally, we found that DC sensing of HIV-1 and HIV-2 required the DNA sensor cGAS. Thus, the HIV capsid is a determinant of innate sensing of the viral cDNA by cGAS in dendritic cells. This pathway might potentially be harnessed to develop effective vaccines against HIV-1. [Display omitted] •Human dendritic cells sense the cDNA of HIV-2 before integration•The HIV-1 capsid allows the virus to escape sensing of its cDNA by dendritic cells•Dendritic cells sense capsid-mutated HIV-1 without replication and stimulate T cells•The DNA sensor cGAS is essential in human dendritic cells for sensing HIV-1 and HIV-2