An Ounce of Tat Prevention Is Worth a Pound of Functional Cure.

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Infection by HIV-1 can effectively be suppressed by antiretroviral therapy (ART). However, the persistence of a small, latent virus reservoir impedes viral eradication. Thus, most infected individuals must be treated with ART for life. While efforts to find a sterilizing cure that eradicates the virus are ongoing, an alternative approach deemed a functional cure has remained less explored. A functional cure for HIV is envisioned as long-term control of virus replication in the absence of ART (reviewed in references 1 and 2). Such a functional cure might encompass effective immune interventions, reduction of the reservoir to a highly “controllable” size, and/or induction of a long-lasting suppression of viral gene expression. The Tat viral protein is a strong transactivator of viral gene expression, and viral replication is severely restricted in its absence; thus, it makes a logical antiviral target. A recent article by Mousseau et al. (3) reports on a novel Tat inhibitor that the authors show has the unusual ability to induce a “permanent state of latency.” Didehydro-cortistatin A (dCA) is a departure from current FDA-approved antiretroviral drugs in that it inhibits viral gene expression from integrated viruses. For the above reasons, dCA represents a novel inhibitor class. Cortistatin A (CA) is a steroidal alkaloid from Corticium simplex , a marine sponge, which has raised interest based on its antiproliferative effects (4). dCA is a derivative of CA that was reported to be equipotent (5) to the parent compound as well as relatively easy to obtain by chemical synthesis. One of the salient features of CA is its ability to bind to and inhibit cyclin-dependent kinase 11 (CDK11) with nanomolar affinity (6). CDK11 was recently shown by Valente and colleagues to be essential for HIV-1 gene expression by phosphorylating factors required for proper 3′ processing of viral mRNAs (7). Based …