amfAR-funded scientist Dr. Brad Jones of George Washington University in Washington, DC, has discovered an obstacle to the “shock and kill” strategy for curing HIV that may have implications for the success of this approach in the clinic.
“Shock and kill” involves using drugs to “shock” latent virus out of hiding so that it can be killed by the immune system or interventions such as a therapeutic vaccine or broadly neutralizing antibodies. In the February issue of The Journal of Clinical Investigation, Jones and colleagues report that the latent HIV reservoir resists attack by CD8 T cells, immune cells charged with clearing virally infected cells.
The authors note that shortly after a person becomes infected, HIV begins to accumulate mutations. As a result, over 88% of viral genes are so defective they are unable to produce infectious virus. However, the reservoir makes up a tiny fraction of the remaining 12% of infected cells and harbors intact genomes capable of producing infectious virus.
Previous ”shock and kill” strategies aimed to reawaken this latent reservoir with drugs called latency-reversing agents (LRAs) to expose the infected cells to the killing power of the immune system. (View amfAR’s explanatory video here.) However, Jones’s research shows that even after reactivation of the reservoir, CD8 T cells prefer to kill cells infected with defective virus and thus have little effect on the reservoir. Even more intriguing, the scientists found evidence to suggest that the reservoir cells, when attacked by CD8 T cells, somehow shield themselves from their deadly onslaught.
At a December scientific conference in Miami, Jones presented related findings pointing to a drug that could make the reservoir more susceptible to killing in a “shock and kill” context. In this “prime, shock and kill” strategy, a drug is given to the patient to prime, or prepare, the reservoir to submit to being killed by CD8 T cells. Then, just as with “shock and kill,” LRAs are added to reawaken the reservoir and mark those cells for killing by the immune system.
“Overall,” Jones said, “I remain very optimistic about “shock and kill” … I just think we may be missing an extra piece of the puzzle. We may have more success with ‘prime, shock and kill.’”
While more work needs to be done to improve “shock and kill,” such as developing more potent LRAs, Jones’s findings could help improve the effectiveness of this strategy.
Dr. Flores is amfAR’s associate director of research.