Scientists have shown how a compound derived from the marine sponge Corticium simplex can virtually eliminate HIV from infected cells, including T cells that act as reservoirs of HIV production in patients undergoing anti-HIV therapy. The Scripps Research Institute researchers say their synthetic version of the sponge’s natural steroidal alkaloid compound cortistatin A (CA) works by selectively inhibiting Tat-mediated transactivation of HIV provirus that has already been integrated into the host cell.
More specifically, the didehydro-cortistatin A (dCA) compound binds to the TAR-binding domain of Tat and prevents Tat-mediated transcriptional initiation/elongation from the viral promoter, so inhibiting both HIV-1 and HIV-2 replication in acutely and chronically infected cells. Importantly, the team’s in vitro studies showed that at nanomolar concentrations the compound just about completely blocked the production and release of HIV particles from the HIV-replenishing CD4+ T cells taken from patients receiving highly active antiretroviral therapy (HAART).
“We know that there are reservoirs of HIV that aren’t being eliminated by current treatment and that keep replenishing the infection,” explains Susana Valente, Ph.D., who headed the research published in Cell Host and Microbe. “Viral production from these cellular rreservoirs that harbor an integrated viral genome is not affected by current antiretroviral drugs, which only stop novel rounds of infection. The compound in the current study virtually eliminates all viral replication from aready-infected cells where HIV hides.”
The Scripps researchers suggest dCA represents a unique class of anti-HIV drug that inhibits viral production from cell reservoirs and could reduce residual viremia in patients undergoing HAART. Their published paper is titled “An Analog of the Natural Steroidal Alkaloid Cortistatin A Potently Suppresses Tat-Dependent HIV Transcription.”
They claim the compound appears to be the most potent anti-Tat inhibitor described to date. “Importantly, dCA has a drug-like structure, is highly soluble in water, and displays good bioavailability in mice,” they state. “dCA treatment was extremely successful at reducing viral production by a drastic 99.7% from primary CD4+T cells isolated from aviremic patients who had been under HAART treatment for a long period of time. Furthermore, by acting additively with other antiretrovirals, dCA further reduced by 20% viral replication from CD4+T cells isolated from viremic patients ... Thus, dCA defines a unique class of anti-HIV drugs that may inhibit viral production from stable reservoirs and reduce residual viremia during HAART.”