A new type of drug, called a toll-like receptor 7 (TLR7) agonist, was able to activate HIV-infected CD4 cells from HIV-positive donors on antiretroviral therapy (ART), leading to the release and replication of virus, according to a presentation at the 2015 Conference on Retroviruses and Opportunistic Infections (CROI) in Seattle, WA. Even more exciting, a second study showed that the same drug not only activated cells when given to monkeys infected with the monkey version of HIV, it also lowered the amount of viral DNA within cells. Together, these studies show that the TLR7 agonist is perhaps the most promising drug to come along that could help us “kick” the virus out of cells, so that the body’s immune system can “kill” those infected cells.
Toll-like receptors are receptors on immune system cells that, among other things, can result in the production of proteins that regulate the immune response to viruses, bacteria and other pathogens. In recent years, scientists have begun to characterize the function of these receptors.
TLR7 has been implicated in auto-immune responses (where the body attacks itself), so it is something of a surprise that the TLR7 agonist being studied by Gilead appears to be safe to use. The drug, called GS-9620, is already in Phase II studies as a treatment for hepatitis B, and experience with the drug led scientists at Gilead to believe that it might be effective in a kick-and-kill model aimed at reversing HIV latency.
Study in human cells
Scientists at the Ragon Institute, in Cambridge, MA, took the blood cells of four HIV-positive individuals on ART. Those cells, treated with ART, were incubated for four days with either GS-9620 or a controlled substance (DMO), and were then analyzed for the production of new copies of viral RNA.
The researchers found that HIV RNA levels rose significantly in three of four of the donor cells incubated with GS-9620. Given that the standard HIV treatment strategy is to reduce HIV levels, it might seem counterintuitive that you would want more virus in this case. But increased RNA levels are one sign that the inactive cells harboring the hidden HIV have begun to actively make virus and would thus be more susceptible to being killed.
Study in non-human primates
The second study presented data on 10 monkeys on ART that were infected with simian immunodeficiency virus (SIV), and that were randomized to receive either GS-9620 or a placebo. The GS-9620 was given in an escalating dose every two weeks and then continued at the highest level every two weeks for several more weeks.
Researchers found that SIV RNA levels significantly increased by the third dose and continued to be elevated at later time points. When the scientists looked at SIV DNA levels in multiple tissues they found significant reductions compared with the placebo.
An early phase I safety study has been started in HIV-positive humans on ART.
Sloan, et al. “TLR7 Agonist GS-9620 Activates HIV-1 in PBMCs From HIV-Infected Patients on cART”. 2015 CROI.
Whitney, et al. “Treatment With a TLR7 Agonist Induces Transient Viremia in SIV-Infected ART-Suppressed Monkeys”. 2015 CROI.