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

Molecular Pathogenesis Program, The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, New York 10016, USA.
Nature (Impact Factor: 41.46). 09/2010; 467(7312):214-7. DOI: 10.1038/nature09337
Source: PubMed


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.

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Available from: David Levy, Dec 13, 2013
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    • "Dendritic cells are therefore not permissive to a full HIV-1 replication cycle, even when SAMHD1 restriction is suppressed. An initial study suggested that this is because the virus is detected by innate sensors acting after viral integration and detecting a complex between the HIV-1 gag protein and the cellular gag-binding cofactor CypA (Manel et al., 2010). However, a more recent study from this group proposed that, in fact, if SAMHD1 is inactivated with Vpx, then the cytoplasmic DNA sensor cGAS detects HIV-1 reverse transcription products, leading to activation of innate signaling cascades and the maturation of the dendritic cells (Lahaye et al., 2013). "
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