SIV reservoir depletion and clearance from neonatal macaques following transient CCR5 depletion

Antiretroviral therapy (ART) suppresses viraemia in people with human immunodeficiency virus (HIV), but HIV provirus persists indefinitely in CD4-expressing cells. Cells containing active provirus express viral proteins and have been successfully targeted using broadly neutralizing antibodies (bnAbs). In contrast, cells containing latent provirus cannot be specifically targeted without latency reactivation. Meaningful depletion of the latent HIV or simian immunodeficiency virus (SIV) reservoirs has not been demonstrated except with cytotoxic conditioning for bone-marrow transplantation. Here we show that both the active and latent SIV reservoirs can be eliminated from infant macaques via profound but transient depletion of cells that express CCR5 using a single shot of CCR5/CD3 bispecific antibody. Neonatal rhesus macaques were infected with SIVmac251, then treated with ART beginning at 1 week after infection, followed by treatment with either a CCR5/CD3-bispecific or a CD4-specific antibody, both of which depleted target cells and accelerated the decline in plasma viraemia. Upon ART cessation, while rebound occurred quickly in all animals treated with ART alone, most animals treated with CCR5/CD3 bispecific antibody remained aviraemic for >3 months. Several remained aviraemic to the end of follow-up and efforts to detect replication-competent virus were unsuccessful. Our results show that bispecific antibody treatment achieves meaningful depletion of the replication-competent SIV reservoir and supports the possibility that clinically meaningful depletion of the HIV reservoir might be achievable for recently infected individuals.