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

Abstract

Dendritic cells (DC) serve a key function in host defense, linking innate detection of microbes to the activation of pathogen-specific adaptive immune responses( 1, 2). Whether there is cell-intrinsic recognition of HIV-1 by host innate pattern-recognition receptors and subsequent coupling to antiviral T cell responses is not yet known( 3). DC 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). We show here that, when DC resistance to infection is circumvented( 7, 8), HIV-1 induces DC 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 (CA) with cellular cyclophilin A (CypA) and the subsequent activation of the transcription factor IRF3. Because the peptidyl-prolyl isomerase CypA also interacts with CA to promote HIV-1 infectivity, our results suggest that CA conformation has evolved under opposing selective pressures for infectivity versus furtiveness. Thus, a cell intrinsic sensor for HIV-1 exists in DC and mediates an antiviral immune response, but it is not typically engaged due to absence of DC infection. The virulence of HIV-1 may be related to evasion of this response, whose manipulation may be necessary to generate an effective HIV-1 vaccine.