A cryptic sensor for HIV-1 activates antiviral innate immunity in dendritic cells

• Published in: Nature (London) 2010-09, Vol.467 (7312), p.214-217
• Main Authors: Littman, Dan R, Manel, Nicolas, Hogstad, Brandon, Wang, Yaming, Levy, David E, Unutmaz, Derya
• Format: Article
• Language: English
• Subjects: 631/250/255/1901; 631/250/262; 692/698/1543/1565/133; Activation; AIDS vaccines; Analysis; Biochemistry, Molecular Biology; Biological and medical sciences; Biological response modifiers; Capsid Proteins - immunology; Cell Line; Cellular immunity; Control; Cyclophilin A - immunology; Dendritic cells; Dendritic Cells - cytology; Dendritic Cells - immunology; Dendritic Cells - metabolism; Dendritic Cells - virology; Fundamental and applied biological sciences. Psychology; Health aspects; HIV; HIV (Viruses); HIV infections; HIV Infections - immunology; HIV Infections - virology; HIV-1 - immunology; HIV-1 - physiology; Human immunodeficiency virus; Human immunodeficiency virus 1; Humanities and Social Sciences; Humans; Immune response; Immune system; Immunity, Innate; Immunology; Influence; Interferon; Interferon Regulatory Factor-3 - genetics; Interferon Regulatory Factor-3 - metabolism; Joining; letter; Life Sciences; Lymphocyte Activation; Microbiology; Microorganisms; Monocytes - cytology; multidisciplinary; Mutation; Phosphorylation; Physiological aspects; Properties; Recognition; Replicative cycle, interference, host-virus relations, pathogenicity, miscellaneous strains; Science; Science (multidisciplinary); Sensors; Sensory receptors; T-Lymphocytes - immunology; Vaccines; Virology; Virulence; Viruses
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature09337

Dendritic cells serve a key function in host defence, linking innate detection of microbes to activation of pathogen-specific adaptive immune responses. Whether there is cell-intrinsic recognition of human immunodeficiency virus (HIV) by host innate pattern-recognition receptors and subsequent coupling to antiviral T-cell responses is not yet known. Dendritic cells are largely resistant to infection with HIV-1, but facilitate infection of co-cultured T-helper cells through a process of trans-enhancement. Here we show that, when dendritic cell resistance to infection is circumvented, HIV-1 induces dendritic cell maturation, an antiviral type I interferon response and activation of T cells. This innate response is dependent on the interaction of newly synthesized HIV-1 capsid with cellular cyclophilin A (CYPA) and the subsequent activation of the transcription factor IRF3. Because the peptidylprolyl isomerase CYPA also interacts with HIV-1 capsid to promote infectivity, our results indicate that capsid conformation has evolved under opposing selective pressures for infectivity versus furtiveness. Thus, a cell-intrinsic sensor for HIV-1 exists in dendritic cells and mediates an antiviral immune response, but it is not typically engaged owing to the absence of dendritic cell infection. The virulence of HIV-1 may be related to evasion of this response, the manipulation of which may be necessary to generate an effective HIV-1 vaccine.