Unexpected Mutations in HIV-1 That Confer Resistance to the Tat Inhibitor Didehydro-Cortistatin A

Didehydro-cortistatin A (dCA) is a human immunodeficiency virus type 1 (HIV-1) Tat inhibitor that functions by selectively binding to the RNA binding domain of Tat. In addition to inhibiting viral replication, dCA can drive HIV-1 into a state of “deep latency” in which latent viruses are refractory to reactivation. Mousseau et al. (G. Mousseau, R. Aneja, M. A. Clementz, S. Mediouni, et al., mBio 10:e01750-18, 2019, https://doi.org/10.1128/mBio.01750-18) have now selected dCA-resistant (dCA(r)) viruses in vitro. Remarkably, dCA(r) viruses do not contain mutations in Tat or the viral transactivation-responsive element (TAR) RNA element that is targeted by Tat. Rather, the viruses contain a combination of mutations in the viral long terminal repeat (LTR) and Nef and Vpr proteins that result in an increase in basal RNA polymerase II (Pol II) transcription of integrated HIV-1. Interestingly, dCA(r) viruses may be deficient in the establishment of latent infection because of their elevated basal Pol II transcription. dCA holds promise for strategies to achieve a functional cure of HIV-1 infection and justifies efforts to develop additional Tat inhibitors.