Combo HIV Therapy Targets Latent Reservoir, Delays Viral Rebound

A new potential therapeutic approach involving a combination treatment that targets the latent reservoir delayed viral rebound following discontinuation of antiretroviral therapy (ART) in an animal study.
 
The ability of HIV to become dormant and remain hidden in latent reservoirs with the potential to become active again represents a critical barrier for the development of a cure for the virus. In the study, which was published in Nature, researchers aimed to target the viral reservoir in hopes of activating and eliminating these cells with a 2-pronged therapy approach.  
 
The researchers administered broadly neutralizing antibodies (bNAb) designed to target the infection in combination with agents that stimulate the innate immune system in 44 rhesus monkeys infected with an HIV-like virus. The combination included treatment with GS-9620 (vesatolimod), an oral drug that activates the Toll-like receptor protein, and PGT121, which recognizes and binds to key HIV proteins on the surface of infected cells and triggers other immune cells to destroy the target cell.
 
The monkeys were previously treated with ART for 2 and a half years, starting 1 week after infection. After 96 weeks, the monkeys were divided into 4 groups: 1 group that received no additional treatments, additional groups given only an immune-stimulating agent or only antibodies, and a fourth group given the immune stimulant in combination with bNAb. Once ART was discontinued at week 130, the researchers began monitoring the animals’ blood for signs of viral rebound.
 
All monkeys in the control group and almost all of those given only the immune stimulant rebounded quickly and with high peak viral loads, within a median of 21 days after stopping ART, according to the study. Of those given the combination therapy, 5 out of 11 monkeys did not rebound within 6 months. Additionally, the monkeys that did rebound showed much lower peak viral loads compared with the control group. Monkeys given only the antibodies demonstrate a detectable but modest delay in viral rebound.
 
The researchers found that CD4+ T cells and NK cells were activated in all monkeys that received GS-9620, according to the report. However, this alone was not sufficient to destroy infected cells, because monotherapy did not prevent viral rebound. The researchers suggested that the treatment activated a “shock and kill” approach, in which the GS-9620 treatment activated the CD4+ T cells harboring latent virus, allowing the antibody to target the infected cells.
 
“Together, our data suggest a mechanism by which the combination therapy stimulated innate immunity and rendered infected cells more susceptible to elimination,” Dan H. Barouch, MD, PhD, director of the Center for Virology and Vaccine Research at Beth Israel Deaconess Medical Center, said in a press release. “This study provides an initial proof-of-concept showing a potential strategy to target the viral reservoir.”
 
Next, researchers will need to evaluate whether administration of the combination therapy can produce similar results in humans through clinical trials.
 
References
 
Borducchi EN, Liu J, Nkolola JP, et al. Antibody and TLR7 agonist delay viral rebound in SHIV-infected monkeys. Nature. 2018. https://www.nature.com/articles/s41586-018-0600-6. Accessed October 3, 2018.
 
Combination Therapy Targets Latent Reservoir of HIV [news release]. Beth Israel Deaconess Medical Center’s website. https://www.bidmc.org/about-bidmc/news/2018/10/combination-therapy-targets-latent-reservoir-of-hiv. Accessed October 3, 2018.



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