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Novel drug candidate thwarts HIV reactivation
An analog of a naturally occurring compound derived from marine life may contribute to a functional cure of HIV-1 infection, according to the results of a proof-of-concept study published in mBio.
In 2006, the steroidal alkaloid cortistatin A was isolated from a species of marine sponge, Corticium simplex. Phil S. Baran, PhD, professor and Darlene Shiley Chair in Chemistry at The Scripps Research Institute (TSRI), is credited with synthesizing the compound in 2008. Previous studies have shown that this variant of the natural product — named didehydro-cortistatin A — selectively inhibits the protein Tat, which is responsible for activating transcription of the viral genome and promoting viral amplification, according to researchers.
“Tat is an attractive target for therapeutic intervention, because it is expressed early during virus replication and it has no cellular homologs,” the researchers wrote. “Moreover, direct inhibition of Tat blocks the feedback loop that drives exponential increase in viral transcription and the production of viral particles.”
Susana T. Valente, PhD, associate professor in the department of immunology and microbial sciences at TSRI, and colleagues demonstrated that didehydro-cortistatin A reduces residual levels of viral transcription in infected T cells of HIV patients on suppressive ART, and establishes a near-permanent state of latency, significantly diminishing the virus’ ability to reactivate. This may reduce the time for the elimination of the viral reservoir.
Susana T. Valente
“In latently infected primary T cells isolated from nine HIV-infected subjects being treated with antiretroviral drugs, didehydro-cortistatin A reduced viral reactivation by an average of 92.3%,” study researcher Guillaume Mousseau, PhD, member of the Valente lab team, said in a press release.
Notably, the researchers found that discontinuing the treatment did not result in viral rebound, “suggesting that the HIV promoter is epigenetically repressed.”
“In our proposed model, didehydro-cortistatin A inhibits the viral transcriptional activator, Tat, far more completely, delaying or even halting viral replication, reactivation and replenishment of of the latent viral reservoir,” Valente said in the release.
According to Valente and colleagues, the findings support an alternative approach to the “kick and kill” strategy, which is meant to purge the latent viral reservoir by activating the virus with standard latency-reversing agents and preventing new rounds of infection with ART.
“These results suggest combining a Tat inhibitor with current antiretroviral therapy could achieve a functional HIV-1 cure by forcing HIV into permanent latency," Valente told Infectious Disease News.” – by John Schoen
Disclosure: The researchers report no relevant financial disclosures.