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

Abstract

HIV-1 (human immunodeficiency virus 1) infection fails to induce interferon in the cells that it infects, but the underlying mechanisms involved are undefined. Dendritic cells — immune cells found in skin, mucosa and lymph tissues — mediate the innate detection of pathogens and the activation of other immune cells involved in specific adaptive immunity. But not for HIV. Dendritic cells are resistant to infection by HIV, although they do bind to the virus and are thought to facilitate the infection of T-helper cells. Now it is shown that when the usual block to HIV infection is bypassed in dendritic cells — by exposure to the Vpx accessory protein from the simian immunodeficiency virus SIVmac — HIV does induce a type I interferon response and T-cell activation. The virulence of HIV-1 may be related to its ability to evade innate immunity by staying out of dendritic cells, and the manipulation of that strategy may be of relevance to vaccine design. Human immunodeficiency virus (HIV) fails to induce interferon in the cells that it infects, but the underlying mechanisms are not known. These authors show that the virus can in fact activate the interferon pathway in dendritic cells when the usual block to infection is bypassed. Dendritic cell activation depends on the HIV-1 capsid/cyclophilin A interaction, which is known to have a role in HIV-1 infectivity. Dendritic cells serve a key function in host defence, linking innate detection of microbes to activation of pathogen-specific adaptive immune responses1,2. 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 known3. Dendritic cells are largely resistant to infection with HIV-14, but facilitate infection of co-cultured T-helper cells through a process of trans-enhancement5,6. Here we show that, when dendritic cell resistance to infection is circumvented7,8, 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.