With 34 million people currently living with HIV worldwide, developing a modality to induce an HIV functional cure is a top global health priority. We have recently discovered that 1) broadly neutralizing antibodies are able to potently eliminate the viral reservoir, and 2) that an IL-15 superagonist, ALT-803, is able to both reverse viral latency and activate natural killer cells in vivo. Therefore, we hypothesize that combining ALT-803 with broadly neutralizing antibodies under cover of cART can clear the latent reservoir. To investigate this intriguing idea, in specific aim 1 of the R21, we will establish the ability of ALT-803 to reactivate latent virus in the macaque model of HIV.
In specific aim 2, we will determine if ALT-803 activated NK cells can mediate antibody- dependent cell-mediated cytotoxicity on infected cells. If successful, we will combine ALT-803 with broadly neutralizing antibodies under cover of cART in the R33 phase. Successful completion of these studies could define an entirely new approach to clearing the latent reservoir.
Although antiretroviral drugs can reduce peripheral HIV replication, these drugs are not curative and we currently have the most people ever in history infected. Therefore, an approach to induce a functional HIV cure is desperately needed. Here, we propose to test a novel combination of HIV-specific broadly neutralizing antibodies and an IL-15 superagonist to both reverse viral latency and activate NK cells in order to purge the latent reservoir.
|Webb, Gabriela M; Li, Shengbin; Mwakalundwa, Gwantwa et al. (2018) The human IL-15 superagonist ALT-803 directs SIV-specific CD8+ T cells into B-cell follicles. Blood Adv 2:76-84|