Journal
NATURE
Volume 467, Issue 7312, Pages 214-U104Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nature09337
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Funding
- EMBO
- Cancer Research Institute
- Institut National de la Sante et de la Recherche Medicale
- Howard Hughes Medical Institute
- Helen and Martin Kimmel Center for Biology and Medicine
- National Institutes of Health (NIH) [AI33856, AI28900, U54AI57168, R01AI065303]
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Dendritic cells serve a key function in host defence, linking innate detection of microbes to activation of pathogen-specific adaptive immune responses(1,2). 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(3). Dendritic cells are largely resistant to infection with HIV-1(4), but facilitate infection of co-cultured T-helper cells through a process of trans-enhancement(5,6). Here we show that, when dendritic cell resistance to infection is circumvented(7,8), 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.
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