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

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.
The exposure of monocyte-derived dendritic cells (MDDCs) to GFP-encoding HIV-1 pseudotyped with vesicular stomatitis virus protein G (VSV-G) (hereafter referred to as HIV-GFP(G); multiplicity of infection (MOI) 1-2, see Supplementary [...]