Harnessing CD89+ NK Cells for Novel Therapeutic Interventions Against HIV/SIV

While antiretroviral therapy (ART) can control the replication of human immunodeficiency virus (HIV) and delay disease progression, there is still no cure, and HIV remains a global public health challenge. A better understanding of early and persistent immunological events in HIV infection is critical to inform novel interventions. The majority of current strategies aiming to prevent, control or eradicate HIV rely on harnessing effector functions of cytotoxic T cells, helper T cells, B cells and antibodies to attack HIV and HIV-infected cells. However, natural killer (NK) cells might represent another subset for therapeutic modulation. Recently, our lab has carried out in-depth, yet preliminary research into NK cells expressing the IgA receptor, CD89, using both human and nonhuman primate samples. We have generated preliminary data showing that: (i) CD89+ NK cells can be readily identified in various tissues including peripheral blood and mucosal tissues; (ii) CD89+ NK cells display an altered signaling phenotype compared to CD89- NK cells; (iii) CD89+ NK cells are significantly restricted in their activation potential; and (iv) CD89+ NK cells can be identified through multiplex imaging indicating their relevant proximity in the GI mucosae. Collectively these data form the basis for our overarching hypothesis that CD89 acts as an inhibitory checkpoint to regulate NK cell mucosal functions, and, therefore, may serve as an attractive target for NK cell-based interventions and therapeutics in lentivirus infections. We will test this hypothesis through two focused Exploratory Aims: (i) Characterize the role(s) and functional regulation of CD89+ NK in the mucosae in normal and SIV/SHIV-infected macaques; and (ii) Investigate the role of autologous CD89+ NK cells in therapeutic modulation of SIV infection. Ultimately, this knowledge has the potential to inform strategies to tune CD89+ NK cells for preventive or therapeutic interventions and personalized treatments, vaccine development, and strategies for reducing viral reservoirs.