Despite the immense success of anti-retroviral therapy (ART) in reducing HIV replication to very low levels, it fails to eradicate the virus. HIV-1 still persists in latently ifected memory CD4+ T cells in individuals on suppressive ART and these cells represent a long-lasting source of resurgent virus upon ART interruption. The most commonly explored strategy for HIV eradication is dubbed shock and kill, which attempts to purge viral reservoirs using anti-latency agents such as HDAC inhibitors, while simultaneously preventing additional rounds of infection by maintaining ART. Several other strategies have been employed for eradicating the latent HIV-1 reservoir including ART intensification, therapeutic vaccines, gene therapy, and stem cell transplantation. Each approach has its own inherent challenges and none have demonstrated definitive success. An alternative approach, which represents a significant departure from established paradigms of eradicating latent reservoirs, uses therapeutic agents targeting HIV-1 transcription. Rather than activating the endogenous latent reservoir, we propose to drive the residual transcription that occurs during ART into a state of long-term latency or deep latency. We based this proposal on the recent discovery that didehydro-Cortistatin A (dCA), an analog of a natural compound isolated from a marine sponge, potently inhibits Tat-mediated trans-activation of the integrated HIV-1 promoter at nanomolar concentrations. Importantly, dCA drives viral gene expression into an induced state of persistent deep-latency in vitro, refractory to viral reactivation. A Tat-inhibitor treatment combined with ART would be aimed at reducing the size of the latent reservoir pool by blocking ongoing viral replication, reactivation and replenishment of the latent viral reservoir, a key limitation of currnt ART. Here we propose to test dCA in rhesus macaques infected with simian immunodeficiency virus (SIV). We hypothesize that by reducing persistent, low-level virus production from reservoirs, dCA will i) reduce the size of the viral reservoir by preventing its continued replenishment, ii) prevent or at least significantly delay viral rebound upon ART discontinuation, and iii) reduce morbidities associated with persistent levels of immune activation caused by low-levels of virus replication in subjects on suppressive ART. During the R21 project phase we will validate that dCA can be efficiently used to block SIV transcription in primary rhesus macaque CD4+ lymphocytes. Upon successful accomplishment of R21 milestones, we will initiate the R33 phase of the project, which is aimed at determining the impact of combining dCA with ART, and whether dCA may replace ART once virus is transcriptionally suppressed.
The HIV-1 viral protein Tat is a potent activator of HIV transcription and a potential antiviral target. We found that didehydro-Cortistatin A (dCA) is a potent inhibitor of Tat. This application seeks to determine in SIV-infected rhesus macaques whether dCA in combination with antiretroviral therapy (ART) has the ability to inhibit residual virus replication, and after discontinuation of ART, if dCA can inhibit or delay viral rebound.
| Mousseau, Guillaume; Valente, Susana T (2017) Role of Host Factors on the Regulation of Tat-Mediated HIV-1 Transcription. Curr Pharm Des 23:4079-4090 |
