Proteasomal Inhibition Potentiates Latent HIV Reactivation

Despite the success of antiretroviral therapy (ART), ART fails to eradicate the virus and HIV cure has remained beyond the reach of current treatments. ART targets replicating virally infected but not latently infected cells, which have limited expression of factors important for proliferation and cellular activity, including positive transcription elongation factor b (P-TEFb) and nuclear factor kappa B (NF-kappa B). Levels of the cyclin T1 (CycT1) subunit of P-TEFb are low to absent in resting T cells, and treatment with proteasome inhibitors (PIs) increases CycT1 protein levels to those of proliferating T cells. In this study, the clinically approved PI bortezomib reactivated latent HIV in latently infected primary CD4+ T cells. Bortezomib not only increased levels of CycT1 but also activated NF-kappa B. Strikingly, as opposed to most currently researched latency reversing agents (LRAs), bortezomib did not require a second LRA to potently reactivate latent HIV. Effects of bortezomib on resting T cells and reactivation of HIV suggest a possible direction for future attempts to diminish the viral reservoir in HIV+ individuals.