Long-term depletion of KIR3DL01+ NK cells by adeno-associated viral-vectored antibody delivery alters chronic SIV infection

Abstract

Natural killer (NK) cells are key innate effectors during antiviral immune responses, with their activity regulated in part by interactions between polymorphic killer-cell immunoglobulin-like receptors (KIRs) on NK cells and their major histocompatibility complex class I (MHC I) ligands on target cells. In human immunodeficiency virus (HIV) infection, certain KIR and MHC I allelic combinations are associated with enhanced viral control and delayed disease progression. To interrogate the contribution of a common KIR+ NK cell subset to the immune response to simian immunodeficiency virus (SIV) infection of rhesus macaques, we depleted KIR3DL01+ cells using an adeno-associated virus (AAV) vector encoding a KIR3DL01-reactive monoclonal antibody. AAV delivery resulted in high and durable antibody expression with minimal anti-drug antibody responses, leading to sustained depletion of KIR3DL01+ NK cells from blood, lymph nodes, and gut-associated lymphoid tissue for more than nine months. Following intrarectal SIV challenge, there was no difference in peak viremia between the two groups. However, KIR3DL01-depleted animals exhibited a modest increase in chronic viremia, reaching statistical significance at multiple timepoints relative to KIR3DL01+ controls. Phenotypic analysis revealed ongoing NK cell maturation in peripheral blood and lymphoid tissue, accompanied by increased expression of activation and proliferation markers during acute and early chronic infection. An expansion of NKG2D+ NK cells was also observed in chronic SIV infection. These findings suggest that KIR3DL01+ NK cells contribute to the inhibition of SIV replication during chronic infection. Moreover, they demonstrate the feasibility of AAV-vectored antibody delivery for long-term, perhaps indefinite depletion of a lymphocyte subset in a nonhuman primate model.