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A novel HIV-Envelope specific bi-specific killer engager (BiKE) enhances natural killer cell response to HIV-infected targets Zachary Davis, PhD; Todd Lenvik, Louis Hansen, Ashley Haase, MD; Timothy Schacker, MD; Jeffrey Miller, MD While advancements in efficacy and use of anti-retroviral drugs have substantially ameliorated the health and longevity of HIV-infected individuals, these drugs are merely a stop-gap to prevent progression to AIDS and to limit further transmission of the virus. Due to HIV’s errorprone replicative process which frequently results in alterations to the proteins that constitute its viral envelope, the normal antibody response to HIV is unable to keep pace with viral mutation and is therefore insufficient to target and clear the virus. In recent years, a clone of anti-HIV Env antibody (VRC01) was identified and isolated from the serum of HIV-infected patients that has broad binding specificity to a wide variety of primary HIV strains. However, this antibody clone, while exhibiting a strong neutralizing capacity, showed little to no ability to mediate an ADCC response necessary to eliminate infected cells. Cellular responses to HIV-infected cells are also dampened by viral alterations of surface expressed ligands on infected cells. Natural killer (NK) cells, which mediate cytotoxic and cytokine secreting functions in response to recognition of germ-line encoded ligands do respond to HIV-infected cells but exhibit significantly diminished responses due to HIV’s selective retention of MHC-I, which act as inhibitory ligands to NK expressed inhibitory receptors, and down-modulation of co-activation ligands. However, NK can mediate ADCC through the low affinity Fc receptor, CD16, which when triggered is able to overcome inhibition by NK inhibitory receptors in order to respond to antibody coated targets. As such, the VRC01 antibody clone is a prime candidate for inclusion our a bi-specific killer engager (BiKE) platform in combination with an anti-CD16 component which would allow for NK targeting and killing of HIV-infected cells expressing HIV Env on their membranes. Here we show our novel construct binds directly to HIV-infected cells and engages CD16 on NK cells to trigger NK cytotoxic and cytokine secreting functions.