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+ 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+ T cell clearance of CD4+ 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+ T cells. Moreover, DARTs mediated CD8+ T cell clearance of HIV from resting CD4+ 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.
Sung, JAM; Pickeral, J; Liu, L; Stanfield-Oakley, SA; Lam, C-YK; Garrido, C; Pollara, J; LaBranche, C; Bonsignori, M; Moody, MA; Yang, Y; Parks, R; Archin, N; Allard, B; Kirchherr, J; Kuruc, JD; Gay, CL; Cohen, MS; Ochsenbauer, C; Soderberg, K; Liao, H-X; Montefiori, D; Moore, P; Johnson, S; Koenig, S; Haynes, BF; Nordstrom, JL; Margolis, DM; Ferrari, G
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