When asked what inspired her to test a derivative compound from a saltwater sponge against HIV replication, investigator Dr. Susana Valente laughed.
“It was luck,” explained the lifelong molecular virologist. She had been working on HIV RNA processing, and had heard that didehydro-cortistatinA (dCA) could play an inhibitory role. When she tested it, her data suggested dCA didn’t inhibit RNA processing, but RNA transcription itself. This led to studies of dCA interaction with the HIV protein Tat, which were written up in a 2012 publication from Cell Host and Microbe.
Tat is a key protein in HIV replication. HIV is a single-stranded RNA virus, but its RNA is turned into DNA and integrated into the host cell DNA – meaning that once infected, there is no way to “cure” an infected cell of the viral DNA. To make more virus, the HIV DNA is transcribed into RNA, which is then packaged into progeny virons. Tat acts as a transcriptional activator during this process, recruiting the host cell proteins necessary to generate many copies of RNA. dCA binds to Tat, blocking its ability to bind and activate high RNA copies.
The authors tested several types of latently-infected immortalized cell lines to compare treatment of an antiretroviral (ARV) drug cocktail with dCA to ARV without dCA. They found dCA addition decreased both the detectable viral particles and viral RNA produced.
These dCA-treated cells mimic latently-infected cells, which exist naturally in the host without producing virus. But unlike naturally latent infections, dCA-treated cells don’t reactivate virus production, even after cell stimulation. In fact, the dCA treated cells are so strongly silenced, the cells were resistant to these stimulations even after the treatment was stopped – up to 150 days after drug removal. The same results were found in HIV-infected patient samples.
These results point to a fundamental effect of dCA on HIV replication, which the authors posit is due to a change in epigenetic regulation of the viral DNA. Epigenetics, or non-mutational changes in DNA structure, affect how accessible the DNA is to the cellular machinery responsible for making RNA.
“Cells are infected but they aren’t expressing anything,” explains Dr. Valente, of infected cells treated with dCA. Dr. Valente hypothesizes the dCA “accelerates the latency through epigenetic inactivation so strong that it takes a very strong activation to initiate virus production.”
The implications of this discovery are multifold. First, this would add a potentially new class of anti-HIV drugs to the already existing arsenals. Second, this would be only the second class of therapeutics to target already-infectedcells, rather than halting the virus as it attempted to infect a new cell. Third, the long-term effects give rise to potential for a change in treatment schedule, with the possibility of treatment cessation or pauses.
How dCA could be realized in antiviral therapy application isn’t yet known. The compound may be added to current ARV regimens. The long-lasting effects of dCA may allow changes in ARV scheduling, facilitating holidays or temporary breaks. “We may eventually reduce the size of the reservoir and eventually achieve a level where the immune system is in check,” says Valente of the best-case scenario. Mouse and macaque experiments are ongoing and will be more revealing for a potential role in chemotherapy.
Tat is a multifunctional protein with many interactions. In addition to its role as a transcriptional activator, Tat is responsible for neurodegeneration associated with HIV infection, and Valente is optimistic about anti-Tat therapy: “Blocking activity of this protein is going to have a lot of overall impact.”
-- Julie Wolf