Miranda Smith
Stronger together: promising combination approach in monkeys
A promising study of a combination approach to HIV cure featured at last month’s Conference on Retroviruses and Opportunistic Infections in the US.
The study looked at the impact of a broadly neutralising antibody (bNAb) together with an immune-activating compound in monkeys. Headed by Dan Barouch from the Beth Israel Deaconess Medical Center in Boston, the researchers showed that the two compounds together delayed the re-emergence of virus when treatment was stopped in infected monkeys with long-term viral control.
The bNAb used in the study was PGT121. PGT121 is a potent antibody that binds sugar residues on the HIV envelope (the V3 loop of gp120, if you’re curious). Previous PGT121 studies showed that a single dose profoundly reduced virus in untreated monkeys with high viral loads.
The second, immune activating, component of the study was GS-9620. GS-9620 is a compound that selectively activates Toll-like receptor 7 (TLR7). TLR7 is a receptor involved in triggering immune responses to viruses including HIV. Researchers have shown that GS-9620 can drive HIV out of its latent state.
How was the study set up?
Researchers infected 44 rhesus macaques with a virus called SHIV. SHIV is a hybrid between the Simian (monkey) and Human Immunodeficiency Viruses. The monkeys started antiretroviral treatment (ART) one week later and quickly controlled the virus to undetectable levels. After nearly 2 years on treatment, the researchers divided the monkeys into four groups. One group was given sham infusions and acted as the control group. One group was given 10 doses of the TLR7 activator every 2 weeks. A third group was given 5 infusions of the bNAb, and the final group was given both the TLR7 activator and the bNAb. ART continued during the dosing procedures and for another four months afterwards, then treatment was stopped.
What happened?
As expected, in all the control animals, the virus came back within about three weeks. In contrast, monkeys given the TLR7 activator/bNAb combo had a long delay (around three and a half months) before the virus rebounded. When the virus did return in this group, it was at a much lower level than in control animals. In nearly half of the animals given the combo, the virus didn’t re-emerge even after 6 months. Monkeys in the groups given either the TLR7 activator or bNAb alone had results similar to controls, although one or two animals in each group remained undetectable.
To see if virus remained in the combo group monkeys without virus rebound, the researchers took lymph node cells from these animals and gave them to uninfected monkeys. The uninfected monkeys remained uninfected.
What does all this mean, and where to next?
These results are encouraging. They show that combining precise immune activation with a potent bNAb can lead to viral remission (and possibly even eradication). It is not clear how long the effect will last. Although the animals were followed for 6 months, very small amounts of virus could remain.
Knowing how the two agents work to reduce the HIV reservoir is a key next step. It is thought that the TLR7 activator activates virally-infected cells, leading to virus production. These activated, infected cells are then targeted by the bNAb which binds to the cell surface. This binding flags the cell for clearance by phagocytosis. Detailed understanding of how these compounds work together will help identify why some animals had delayed rebound and others had none in the study period.
There are plenty of other remaining questions. Would this strategy be effective in monkeys who start treatment later? What about those who have periods of uncontrolled viral replication? Crucially, would the same effect occur in humans with HIV? Definitely keep an eye out for this work. Hopefully there will be some updates at the Amsterdam 2018 International AIDS conference in July.
For more details, watch the presentation from CROI, or read the conference abstract.
.png)