The key, then, is a compound that targets only the "safe haven" cells. One potential drug is prostratin, a compound isolated from a Samoan medicinal plant that revs up CD4 cell division. Prostratin is more effective when used with both HDAC inhibitors and with 5-aza-2'deoxycytidine. This synergy allows the drugs to be used at lower concentrations, thereby reducing toxicity, and could "increase the chances that only the virus is reactivated," Verdin says. He explains that HDACs, methylation and prostratin regulate different sets of genes; only those genes under the control of all three would fully awaken. "There are incredible synergies between the classes of drugs," he says. "This is the wave of the future."
Toxicities are unlikely to be completely eliminated but, as Siliciano suggests, researchers could start looking at eradication strategies similar to cancer chemotherapy and "accept a fair amount of toxicity." A new study in Nature Medicine by a team of Canadian and U.S. researchers actually describes a cancerlike therapy using targeted chemotherapy, along with HAART to attack both the viruses circulating in the body and those playing hide-and-seek. (Scientific American is part of the Nature Publishing Group.)
A long way to go before trials
Even if researchers find a reasonably safe drug candidate, clinical trials could be difficult given that the only way to truly determine if eradication is complete is to take a patient off HAART—a potentially dangerous and unethical risk. This quandary has inspired some researchers to add macaques as test subjects, although those animals are not void of drawbacks, either. "One has to collect a lot of cells to measure the latent reservoir," Richman says, noting that fewer than one cell in a million is latently infected. "That's a challenge in a big human, but an even greater challenge in a much smaller monkey."
As if these obstacles were not enough, latent CD4 cells may not even be the only hideout for HIV. "One should never underestimate one's enemy," Richman warns, noting other places the virus could theoretically hide, including macrophages or stem cells.
At this point, the research is still aimed at understanding the mechanisms. Richman predicts that any therapy that could rouse all the HIV in a patient's body and successfully eliminate it is still a decade or two away. "It's still a bit of a dream," he says, "but one has to be an optimist in this business."