Targeting Tim-3 for elimination of HIV reservoirs

Award amount: 222,000.00

This study is aimed at determining whether targeting a novel immune-inhibitory pathway can deplete latently HIV infected CD4 memory T cells in HIV virally suppressed patients. Although antiretroviral therapy (ART) can suppress HIV replication and significantly improve the long-term health of the patient, it is unable to permanently remove latent reservoirs of virus. Therefore, novel strategies are needed to specifically target and destroy latently infected cells. The T-cell immunoglobulin and mucin domain?containing molecule 3 (Tim-3) receptor is an inhibitory molecule upregulated during chronic infections and marks dysfunctional and anergic T cells. We have shown that HIV-specific T cells expressing Tim-3 no longer respond to antigen. Strikingly, Tim-3 blockade restores full effector T cell function. In our preliminary studies we find increased Tim-3 expression on dysfunctional CD8+ T cells in lymph nodes of SIV infected rhesus macaques indicating that the Tim-3 pathway is active in the non-human primate model. With the development of (1) Tim-3 mAb/Fab (2) a novel HIV latency assay and (3) an anti-retroviral therapy regimen that consistently and potently inhibits SIV replication, we propose to determine whether targeting the Tim-3 immune-inhibitory pathway can deplete latently HIV and SIV infected CD4 memory T cells and serve as a novel HIV eradication approach.