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. Emerging immune checkpoint leukocyte immunoglobulin‐like receptor B1 (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. Here, 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. Pharmacodynamic 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 + plasmacytoid dendritic cells (pDCs) and CD80 + monocyte/macrophage subsets in blood and lymphoid tissues. These changes were accompanied by increased plasma levels of interferon lambda (IFN‐λ), IL‐8, 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 data show that LILRB1/B2 blockade modulates early myeloid activation and is associated with enhanced SIV‐specific memory CD8+ T‐cell responses. These findings support further evaluation of LILRB1/B2 blockade as part of combination immunotherapeutic strategies in settings such as ART‐treated infection and analytical treatment interruption.