HIV ‘shock and kill’ strategy may put brains at risk

Brain cells from an SIV-infected macaque treated with ingenol and vorinostat. Macrophages are marked green and the virus red; virus-infected macrophages appear orange/yellow. Blue marks the nuclei of all cells. (Credit: Stephen Wietgrefe/U. Minnesota)

A proposed strategy for curing HIV infection rather than just suppressing the virus may actually put patients’ brains in danger, tests in monkeys suggest.

Research using HIV’s close cousin, simian immunodeficiency virus, finds that the so-called “shock-and-kill” strategy could backfire and make things worse if dormant virus is lurking in the brain.

“Our study sounds a major cautionary note about the potential for unintended consequences of the shock-and-kill treatment strategy,” says Janice Clements, professor of molecular and comparative pathobiology at Johns Hopkins University School of Medicine.

Combination drug treatments now in use can control infection by HIV, the virus that causes AIDS. But the goal of totally wiping out the virus and curing patients has been stymied by HIV’s ability to hide out in cells and become dormant for long periods of time.

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The idea of shock and kill is to use so-called latency-reversing agents to wake up dormant virus, making it vulnerable to a patient’s immune system. This, in combination with antiretroviral medicines, would wipe out the majority of infected cells.

But the new study of macaques with SIV, published in the journal AIDS, indicates that the strategy could lead to potentially harmful brain inflammation.

Researchers were concerned that the promising technique of “waking up” dormant virus could be a problem if some of that HIV was in reservoirs in the brain, says lead author Lucio Gama, assistant professor of molecular and comparative pathobiology.

The idea that HIV can enter and affect the brain had come from many cases of AIDS dementia before the current antiretroviral cocktail treatment was developed. But no studies had definitively answered whether significant amounts of latent HIV could remain in the brains of patients taking long-term antiretroviral drug therapy.

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For the new study, researchers treated three pig-tailed macaque monkeys infected with SIV with antiretrovirals for more than a year. Then the two of the macaques were given ingenol-B, a latency-reversing agent thought to “wake up” the virus.

“We didn’t really see any significant effect,” Gama says, “So we coupled ingenol-B with another latency-reversing agent, vorinostat, which is used in some cancer treatments to make cancer cells more vulnerable to the immune system.” The macaques continued receiving antiretrovirals throughout the experiment.

After 10 days of the combined treatment, one macaque remained healthy, but the other developed symptoms of encephalitis, or brain inflammation, Gama says, and blood tests revealed active SIV infection. Testing revealed SIV was present in the brain, but only in one of the regions analyzed: the occipital cortex, which processes visual information. The affected area was so small that “we almost missed it,” he says.

Gama cautions that the study with macaques with SIV may not apply to humans with HIV. It’s also possible that the encephalitis was transient and could have resolved by itself. Still,Gama says the results signal a need for extra caution in exploring ways to flush out HIV reservoirs and eradicate the virus from the body.

Other coauthors are from Johns Hopkins, the University of Minnesota, the University of Wisconsin, Kyolab in Brazil, the Université Libre de Bruxelles in Belgium, and the LRA-SIV Study Group.

The National Institutes of Health, the France Recherche Nord & Sud Sida-HIV Hépatites, the Belgian Fund for Scientific Research, the Fondation Roi Baudouin, the NEAT program, and the Walloon Region (the Excellence Program Cibles) funded the work.

Source: Johns Hopkins University