By Andreas von Bubnoff
Researchers have in the past few years found many new broadly neutralizing antibodies (bNAbs) that are often much more potent and broadly effective against HIV than the few that were available before 2009. One goal now, of course, is to develop a vaccine that can elicit these bNAbs. But researchers are also interested in using them to treat HIV infection. Last year, they reported for the first time that a cocktail of several bNAbs could for some time suppress HIV replication in mice that carry human immune cells.
Now researchers report even more impressive effects of this approach in rhesus macaques chronically infected with SHIV, a monkey variant of HIV that carries the HIV envelope protein on its surface, suggesting that bNAb treatment might even work in HIV-infected humans. In two studies, researchers showed that injecting a cocktail of two or three bNAbs could lower viral loads to undetectable levels within a week. The effect lasted several weeks to several months and was dependent on the continued presence of the infused antibodies in the body.
In one study, led by Dan Barouch of Beth Israel Deaconess Medical Center and the Ragon Institute, administration of just one bNAb called PGT121 kept the virus at undetectable levels for about two months, an effect that was more dramatic than what had been seen in the mouse study last year. “After we did our first experiments, the results were so dramatic that we simply had to do the experiment again a second time to make sure that we all believed the results,” Barouch says. “Even the PGT121 antibody [alone] worked in these monkeys, so it was surprisingly effective,” observes Louis Picker, who was not connected to the studies but wrote a commentary about them in the same issue of Nature, the scientific journal where both studies appeared.
Barouch and colleagues also found that, as expected, the virus resurged once the bNAbs disappeared from the blood of the monkeys. But it reappeared at lower levels. What’s more, the three PGT121-treated animals with the lowest initial virus levels suppressed the virus even after antibody levels had become undetectable. This suggests that the bNAb treatment had improved immune function, and indeed, Barouch and colleagues found that the function of CD4+ and CD8+ T cells was improved in the treated animals.
That’s not to say that there were no limitations of the treatment: PGT121 didn’t fully suppress virus in the animals with the highest initial viral loads. And in the other study, led by Malcolm Martin of the National Institute of Allergy and Infectious Diseases, some animals became resistant to one of the bNAbs used in the experiments. This suggests that researchers may have to combine several bNAbs to make sure resistance is less likely.
The monkey results suggest that the treatment may also work in humans, and Barouch says his group and others are now interested in exploring a number of those antibodies in clinical trials.
Still, Picker says, the question is whether bNAb treatment will add anything to current antiretroviral therapy regimens for routine treatment of HIV infection, given that current antiretroviral drugs can keep virus levels undetectable by just taking a pill a day and can enter the CNS; in contrast, generating the bNAbs of the high quality needed for human use isn’t cheap, and the antibodies have to be injected and potentially can’t enter the CNS.
But Martin says that bNAbs might be useful in certain situations where one can’t use drugs, such as in people resistant to all drugs, or in newborns. What’s more, some of the effects of bNAbs go beyond those of antiretrovirals (ARVs). In the monkey studies, bNAbs seemed to suppress virus to undetectable levels faster than do ARVs. That’s probably because unlike ARVs, bNAbs can eliminate free HIV from blood.
Also unlike ARVs, bNAbs can mediate the killing of infected cells by other parts of the immune system once they bind to HIV proteins some infected cells display on their surface. One indication that this might be happening is that Barouch and colleagues found that the antibody treatment reduced the number of cells with integrated HIV DNA in blood, lymph nodes and gut lining of the monkeys.
Because bNAbs can kill HIV-infected cells, Picker says they might also be able to lower the residual virus burden in people on highly active antiretroviral therapy, which could help reduce the chronic virus-related inflammation that is thought to contribute to long term complications such as premature aging and accelerated cardiovascular disease.
bNAbs might even help with strategies researchers are developing to cure HIV infection, where the challenge is to get the virus out of its hiding place in latently infected, resting memory CD4+ T cells. These cells harbor integrated HIV DNA in their genome, and one strategy to eradicate this “HIV reservoir” is to activate the latently infected cells so that they produce virus again. These reactivated cells can then be targeted for elimination, and the new studies suggest that bNAbs might be a good way to kill them. “I believe that these antibodies have a definite role in the next generation of strategies that will be evaluated to try to reduce and hopefully eventually eliminate the viral reservoir,” Barouch says.