A trispecific Ab directed to HIV-1 and T cells activates and eliminates latently-infected cells in HIV/SHIV infections

Abstract

Abstract The main barrier to HIV virus eradication is the presence of long-lived HIV-1 that persists in latent reservoirs. Current efforts have focused on HIV cure interventions that “shock and kill” virally infected cells to purge the latent pool. Latency reversing agents (LRAs) induce viral activation leading to immune cell recognition and clearance of latently-infected cells. Though several clinical trials with LRAs have demonstrated that activation of viral gene expression is possible in vivo, limited or no clearance of the reactivated cells has been observed. The identification of molecules that can simultaneously activate latent HIV, increase immune activation and enhance the killing of latently-infected cells represents an alternative promising approach. Here, we developed and evaluated a trispecific antibody that targets three independent proteins: (1) the HIV envelope, (2) the T cell antigen CD3, and (3) the co-stimulatory molecule CD28. For targeting HIV Env, we used the broadly reactive CD4-binding site monoclonal antibody (mAb), N6. We found that an antibody with all three specificities (N6/αCD3-αCD28), significantly increased antigen-specific T-cell activation and cytokine release in both CD4+ and CD8+ T cells. Co-culturing CD4+ T cells with autologous CD8+ T cells isolated from ART suppressed HIV+ donors in the presence of N6/αCD3-αCD28, resulted in activation of latently-infected cells and enhancement of the cytolytic activity of CD8+ T cells to eliminate the cells expressing reactivated HIV. This trispecific antibody mediated CD4+ and CD8+ T-cell activation in non-human primates and was well tolerated in vivo, confirming its activity and safety in a relevant animal model. This HIV-directed antibody is therefore merits further development as a potential intervention for the eradication of latent HIV infection.