The immune system has many different mechanisms for detecting bacteria, fungi and viruses. One such mechanism uses a series of proteins called toll-like receptors (TLR). One of these proteins, called TLR-7, has been the focus of much research. After it senses the genetic material of a virus, TLR-7 helps to activate certain cells of the immune system to respond with the production of antiviral substances.
Vesatolimod (also known under the code name GS-9620) is an experimental drug that interacts with TLR-7. The reason for testing vesatolimod is that researchers hope that by interacting with TLR-7 it can help increase the immune system's ability to sense and attack HIV and HIV-infected cells.
Vesatolimod has previously been tested at relatively low doses in people with chronic hepatitis B virus (HBV) infection. The drug was safe but did not significantly increase cure rates of HBV when used at doses between 1 and 4 mg taken once weekly for 12 consecutive weeks.
From SIV to HIV to SHIV
In susceptible monkeys, simian immunodeficiency virus (SIV) causes an AIDS-like condition. This virus is closely related but not identical to HIV. It is likely that some form of SIV was the ancestor of HIV. However, because there are differences between SIV and HIV, it means that monkeys infected with SIV do not always respond well to drugs designed to treat HIV (ART) or vaccines designed to protect against HIV. Testing ART and vaccines in monkeys is an important step before further testing in humans. To gain a fuller understanding of the response of the monkey immune system to ART and vaccines, researchers have created a hybrid virus using elements of both SIV and HIV. Scientists call the resulting hybrid virus "SHIV" and it has been used for more than 20 years in laboratory experiments with monkeys.
An Important Monkey Experiment
Researchers in the U.S. have conducted experiments with monkeys infected with SHIV. Shortly after infection they gave the monkeys ART. Subsequently, some monkeys received no additional intervention, some received vesatolimod, some received the broadly neutralizing antibody (bNAb) PGT121, and still other monkeys received both vesatolimod and PGT121. Researchers then discontinued giving some of the monkeys ART.
Researchers found that the combination of vesatolimod and PGT121 delayed the resurgence of virus that occurs after interruption of ART. Five of the 11 monkeys given both drugs did not have a resurgence of virus for more than six months after researchers withheld ART. Also, researchers found it difficult to detect virus samples from these five monkeys. The combination of vesatolimod and a powerful antibody has the potential to be tested in HIV-positive people, perhaps allowing them to safely interrupt ART and potentially reducing their burden of HIV-infected cells.
Researchers used 40 monkeys, all of which received ART shortly after infection with SHIV. The monkeys were divided into subgroups and some received additional agents:
- no additional intervention
- vesatolimod + PGT121
Doses of Experimental Drugs
A total of 10 doses of vesatolimod were given orally every two weeks.
Monkeys received five intravenous infusions of the antibody PGT121 every two weeks for about four and a half months.
Eventually the interventions were stopped, the monkeys were monitored and blood samples from all the monkeys were analysed and compared.
Monkeys treated with both vesatolimod and PGT121 had significantly lower levels of SHIV-infected cells in their lymph nodes. This suggests that the combination of these two interventions may be able to reduce the burden of virus-infected cells in the bodies of monkeys with SHIV. Also, monkeys who received both interventions showed a significantly increased delay to the resurgence of virus in their blood after cessation of ART.
Monkeys that had the longest delay in resurgent virus tended to have lower levels of SHIV during their initial infection (prior to treatment with ART). This suggests that SHIV probably did not spread as far in the bodies of monkeys with low viral loads prior to initiation of ART.
Bear in Mind
The results from the monkey studies are very promising. They suggest that a combination of vesatolimod and PGT121 (or perhaps another powerful antibody) can help keep SHIV in check for about six months after cessation of ART in some SHIV-positive monkeys. Also, the combination of drugs has the potential to reduce the burden of SHIV-infected cells in monkeys.
The results from the study in monkeys raise the following possibility:
The combination of vesatolimod and PGT121 could, in theory, allow for an interruption of ART and increase the chances of a cure for HIV in people who respond to this combination.
However, there are at least three aspects of the present study that are cause for caution when interpreting and extending the results of the monkey study to humans:
- Monkeys were treated with ART soon after they were infected. In contrast, historically, most people begin HIV treatment months or even years after HIV infection was diagnosed.
- Monkeys who had a low viral load prior to initiation of ART appeared to be the ones able to respond best to the combination of vesatolimod and PGT121.
- A hybrid virus, SHIV, was used in the experiments. Some researchers have noted that SHIV "is potentially easier for the monkey immune system to control than other monkey viruses."
Despite these caveats, the results of the current experiment have encouraged some researchers to begin planning studies in HIV-positive people with vesatolimod and broadly neutralizing antibodies.
- Borducchi EN, Liu J, Nkolola JP, et al. Antibody and TLR7 agonist delay viral rebound in SHIV-infected monkeys. Nature. Nov;563(7731):360-364.
- Petes C, Odoardi N, Gee K. The toll for trafficking: Toll-like receptor 7 delivery to the endosome. Frontiers in Immunology. 2017 Sep 4;8:1075.
- Agarwal K, Ahn SH, Elkhashab M, et al. Safety and efficacy of vesatolimod (GS-9620) in patients with chronic hepatitis B who are not currently on antiviral treatment. Journal of Viral Hepatitis. 2018 Nov;25(11):1331-1340.
- Sok D, Burton DR. Recent progress in broadly neutralizing antibodies to HIV. Nature Immunology. 2018 Nov;19(11):1179-1188.
[Note from TheBodyPRO: This article was originally published by CATIE on Dec. 7, 2018. We have cross-posted it with their permission.]