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Shock & Kill: Progress in HIV Cure Research

March 23, 2015, by Emily Newman

A new class of latency activator, a TLR7 agonist—used to “shock and kill” HIV-infected cells—has shown promise when tested in animals and represents an exciting development in the HIV cure research field. A fully effective “shock and kill” method would ultimately help people with HIV reduce their viral reservoirs—and achieve a functional cure for HIV.
The “shock and kill” or “kick and kill” approach is the leading effort in HIV cure research at this point in time, said Steven Deeks, MD, a professor of medicine at the University of California, San Francisco (UCSF) and a faculty member in the Positive Health Program at San Francisco General Hospital, during a recent HIV cure presentation hosted by Project Inform.
Latently-infected CD4 cells, part of the so-called “viral reservoir,” have thus-far posed an insurmountable challenge to HIV cure strategies. These cells, while they aren’t actively producing new virus, do contain viral DNA and are able to “hide” from immune system cells that would normally target and destroy them. They’re the reason that HIV is able to rebound, from previously undetectable levels, if successful antiretroviral therapy is stopped.
New research presented by James Whitney, PhD from Beth Israel Deaconess Medical Center, Harvard Medical School at the Conference on Retroviruses and Opportunistic Infections (CROI) in February (abstract 108) showed that a TLR7 agonist—which stimulates immune cell receptors called TLR7—effectively reduces viral reservoirs using the “shock and kill” approach.
Whitney’s team infected Rhesus macaques with simian immunodeficiency virus (SIV), a virus similar to HIV that infects monkeys, and approximately 60 days post-infection, initiated antiretroviral therapy (ART) with tenofovir/emtricitabine/dolutegravir. All of the monkeys quickly suppressed their viral loads to under 50 copies per mL.
About 320 days post-infection, the researchers started giving four of the monkeys escalating doses of the TLR7 agonist. They found that TLR7 reliably produced viremic “blips” when administered at the highest dose (0.3 mg/kg), and that these blips were fairly robust—over 500 copies/mL in all four animals by the fifth dose.  No blips were observed in animals treated with placebo. This means that the agonist successfully “shocked,” or reactivated virus-infected cells from the viral reservoir, bringing them out of hiding from the immune system, to start producing new copies of HIV.
“This was extremely exciting data to us,” said Whitney.
The researchers also measured the agonist’s effect on the immune cells—CD8+ and NK T cells—whose role it is to “kill” SIV-infected cells. Doses of TLR7 led to increased activation of both CD8+ and NK T cells (i.e., greater numbers of these white blood cells were being produced). “There’s a fairly nice dose-response to CD8 activation levels, with a similar pattern of transient yet quite potent NK cell activation as well,” explained Whitney.
When antiretroviral therapy was stopped, viral rebound occurred in both the placebo-treated and TLR7 agonist-treated monkeys. But levels of SIV RNA rebounded to much lower levels in TLR7 agonist-treated monkeys. In other words, TLR7 agonist-treated monkeys controlled virus much better after they stopped treatment.
“There is a very clear reduction in plasma set-point values in the animals that received the TLR7 treatment,” said Whitney, a finding he described as “very interesting.”
Further investigation of peripheral blood mononuclear cells (PBMCs), lymph node, and colon samples found that SIV proviral DNA (a measure of latent or inactive HIV-infected cells) was much reduced in TLR7 agonist-treated monkeys. This finding provides fairly clear evidence that the drug worked well to activate, and reduce, the viral reservoir.
Further clinical research is needed to demonstrate that TLR7 agonists can effectively, and safely, reduce viral reservoirs in people with suppressed viral loads stable on ART. Gilead Sciences announced at the end of February that they will move forward with a TLR7 agonist Phase 2 clinical trial in humans based on the positive results from this study.