Dual-affinity re-targeting proteins direct T cell-mediated cytolysis of latently HIV-infected cells

Enhancement of HIV-specific Immunity Is likely required to eliminate latent HIV Infection. Here, we have developed an Immunotherapeutic modality aimed to improve T cell-mediated clearance of HIV-1-infected cells. Specifically, we employed Dual-Affinity Re-Targeting (DART) proteins, which are bispecific, antibody-based molecules that can bind 2 distinct cell-surface molecules simultaneously. We designed DARTs with a monovalent HIV-1 envelope-binding (Env-binding) arm that was derived from broadly binding, antibody-dependent cellular cytotoxicity-mediating antibodies known to bind to HIV- infected target cells coupled to a monovalent CD3 binding arm designed to engage cytolytic effector T cells (referred to as HIVxCD3 DARTs). Thus, these DARTs redirected polyclonal T cells to specifically engage with and kill Env-expressing cells, including [CD4.sup.+] T cells infected with different HIV-1 subtypes, thereby obviating the requirement for HIV- specific immunity. Using lymphocytes from patients on suppressive antiretroviral therapy (ART), we demonstrated that DARTs mediate [CD8.sup.+] T cell clearance of [CD4.sup.+] T cells that are superinfected with the HIV-1 strain JR-CSF or infected with autologous reservoir viruses isolated from HIV-infected-patient resting [CD4.sup.+] T cells. Moreover, DARTs mediated [CD8.sup.+] T cell clearance of HIV from resting [CD4.sup.+] T cell cultures following induction of latent virus expression. Combined with HIV latency reversing agents, HIVxCD3 DARTs have the potential to be effective immunotherapeutic agents to clear latent HIV-1 reservoirs in HIV-infected individuals.
Introduction The inability of antiretroviral therapy (ART) to eradicate HIV was first suggested by the demonstration of latent infection of resting [CD4.sup.+] T cells (1) and then by the recovery [...]