Targeting the pDC/IFN-I axis in HIV-1 immunotherapy

Purpose of review Recent findings on the critical pathogenic role of inflammatory pDC and type 1 interferons (IFN-I) in HIV-1 pathogenesis in humanized mice and its correlation with inflammatory diseases in people living with HIV-1 (PLWH) suggest that targeting the pDC/IFN-I signaling pathway will reverse HIV-induced inflammation to treat HIV-associated end-organ diseases and rescue anti-HIV immunity to reduce or control HIV-1 reservoirs. Recent findings In both humanized mice and in PBMC from people living with HIV-1 (PLWH), depletion of pDC or inhibition of IFN-I signaling resolves IFN-associated inflammation, rescues anti-HIV T cell functions and reduces HIV-1 reservoir cells. In humanized mice with HIV-1 persistent infection under effective HAART, persistent pDC activation and IFN-I signaling has been shown to induce HIV-associated tissue injury and anti-HIV T cell impairment. in HIV-infected mice with effective HAART, pDC depletion phenocopies what is achieved with blocking IFN-I signaling in reversing HIV-induced inflammation, rescuing anti-HIV T cells and reducing HIV-1 reservoirs. Interestingly, in both humanized mice and in PBMC from PLWH, depletion of pDC or inhibition of IFN-I signaling rescues anti-HIV TCF1+ (T cell factor 1) PD1+ (programmed cell death protein 1) CD8 T cell functions to enhance the effect of PD1 immune checkpoint inhibitor (ICI) to reduce HIV-1 reservoir cells. Summary These findings functionally define the role of the pDC/IFN-I pathway in HIV-associated inflammation, HIV-1 reservoir persistence and end-organ diseases, and suggest that inhibiting pDC or blocking IFN-I signaling will provide a novel therapeutic strategy to reverse inflammation-associated diseases and to rescue anti-HIV immunity that cooperates with PD1 ICI effect to reduce or control HIV-1 reservoirs.