Dual blockade of LILRB1 and LILRB2 enhances antiviral immune responses in SIV infection

Abstract Restoring effective antiviral immunity remains a major challenge in HIV infection. Among emerging immune checkpoint molecules, the inhibitory receptors LILRB1 and LILRB2 have been proposed as therapeutic targets, yet their in vivo function remains undefined due to the lack of cross-reactive blocking antibodies for relevant preclinical models. To address this, we developed a dual-specific blocking monoclonal antibody, mac20G10, targeting cynomolgus macaque LILRB1 and LILRB2 and assessed its immunomodulatory activity in an SIV model of infection. Pharmacodynamics analyses demonstrated that mac20G10 persisted in circulation and engaged target myeloid cells for up to 14 days without detectable adverse effects. A single administration prior to SIVmac251 infection enhanced early myeloid immune activation, characterized by increased frequencies of CD80 + pDC and CD80 + monocyte/macrophage subsets in blood and lymphoid tissues. These changes were accompanied by increased plasma levels of IFN-λ, IL8, and IL-1RA during acute infection. Although viral replication remained unchanged, mac20G10 treatment promoted the development of SIV-specific memory CD8⁺ T-cell responses. Together, these findings provide in vivo evidence that LILRB1 and LILRB2 function as myeloid immune checkpoints restraining antiviral priming, supporting this pathway as a rational target for combination immunotherapeutic strategies aimed at achieving durable HIV remission during analytic treatment interruption.