A Bispecific Biologic That Robustly Reverses HIV-1 and SIV Latency
Huang, Y.; Nair, M. S.; Yu, J.; Chong, S.; Hong, H.; Mohri, H.; Takata, H.; Varco-Merth, B. D.; Marenco, A.; Lifson, J. D.; Ndhlovu, L.; Bowen, A.; Trautmann, L.; Vasan, S.; Chun, T.-W.; Okoye, A. A.; Ho, D. D.
Show abstract
Antiretroviral therapy suppresses HIV-1 replication but cannot eliminate the latent viral reservoir persisting in memory CD4 T cells. Existing latency reversal candidates have yet to achieve robust viral reactivation at tolerable doses. We engineered T4IL15{triangleup}, a bispecific biologic that selectively delivers IL-15 signaling to memory CD4 T cells, with minimal off-target stimulation. T4IL15{triangleup} reactivated latent virus in 94% (48/51) of clinical samples ex vivo, 75% (15/20) of administrations in HIV-1-infected and ART-suppressed humanized mice, and 100% (6/6) of SIV-infected and ART-suppressed rhesus macaques at doses well tolerated. We also found that off-target stimulation of non-CD4 cells hindered HIV-1 reactivation ex vivo. T4IL15{triangleup} provides a robust reactivation platform that could complement other reservoir-elimination strategies toward an HIV-1 cure.
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