KIR/HLA Pleiotropism: Protection against Both HIV and Opportunistic Infections

Abstract

The compound genotype KIR3DS1/HLA-B Bw4-80I, which presumably favors natural killer cell activation, has been implicated in protection against HIV disease. We show that this genotype confers dual protection over the course of HIV disease; early direct containment of HIV viral load, and late specific defense against opportunistic infections, but not AIDS-related malignancies. The double protection of KIR3DS1/Bw4-80I in an etiologically complex disease such as AIDS, along with the disease specificity of its effects is conceptually novel and underscores the intricacy of host immunogenetics against HIV/AIDS. Natural killer (NK) cells are part of the innate immune response which provides the first line of defense against viral infections such as HIV by production of cytokines and direct killing of infected cells. NK cells possess a variety of inhibitory and activating receptors that upon binding to their HLA class I ligands on target cells, regulate activation and inhibition of NK cell responses. A protective effect of the specific combination of the activating receptor KIR3DS1 with HLA-Bw4 alleles that have isoleucine at position 80 (HLA-B Bw4-80I) against AIDS progression was reported previously. Based on this genetic association, KIR3DS1 on NK cells was proposed to bind to HLA-B Bw4-80I on HIV-1 infected target cells, thereby signaling the NK cell to kill the target. Here we present data showing that this compound genotype also confers protection against the development of AIDS defining opportunistic infections. Interestingly, no protection against the development of AIDS defining malignancies was observed. The double protection of this compound genotype in AIDS, along with the specificity of its effects is a novel finding and underscores the complex role of host immunogenetics against HIV/AIDS.