2018 BSJ Blog Fall 2018 featured

HIV-targeting antibodies offer an alternative approach to current HIV treatment, which has toxic side effects

By Isabelle Chiu

HIV is unstoppable, and its current treatment with harmful side effects. But what if we had a way to combat it?

The human immunodeficiency virus, also known as HIV, is a virus that weakens the immune system by attacking a subset of T cells called CD-4+ cells. Severe HIV infections can lead to acquired immunodeficiency syndrome (AIDS), which is lethal. HIV is currently treated with antiretroviral therapy (ART), a drug therapy that uses a concoction of drugs to slow the virus’s development but does not stop it.

ART targets the area where viral replication occurs, in the part of the cell known as the active viral reservoir, and blocks replication. However, it does not target viral reservoirs that exist in a ‘dormant’ state, known as the latent viral reservoir. In latent viral reservoirs, virus replication occurs at a very low rate but it is at risk of increasing in the future. Scientists want to find a treatment that can target these cells for more effective treatments.  

ART also has harmful side effects such as causing higher blood sugar, higher cholesterol, fat redistribution, and loss of bone density. But if ART treatment ceases, the virus is found in the bloodstream within days, an occurrence known as a viral rebound, as the virus starts rapidly reproducing. In this stage, HIV typically quickly progresses into AIDS.

Dr. Pilar Mendoza working at University of Missouri-Columbia and Yotam Bar-On, affiliated with Rockefeller University, have analyzed the effect of combining two HIV-targeting antibodies that can bind to and block Env, a protein on the surface of the virus, to prevent HIV from entering into CD4+ T cells. These antibodies are also known as broadly neutralizing antibodies (bNAbs) and target regions of the Env molecule present in nearly all HIV strains. They block Env, which encodes the viral envelope that protects the virus and allows HIV to enter T-cells. Two such bNAbs tested are 3BNC117 and 10-1074, which have already been tested to be safe by clinical trials, but individually, they had a period of 3-6 weeks before viral rebound.

Mendoza tested whether combining 3BNC117 and 10-1074 would target additional sites on Env, therefore decreasing viral resistance. She gave the two antibodies to 11 people who had temporarily stopped receiving ART. In the beginning, viral levels in the bloodstream drastically lowered, with little evidence of resistance to the antibodies, possibly suggesting it as an alternative to ART. The virus in the bloodstream was practically undetectable for a median of 21 weeks before viral rebound in patients who had been on ART. However, Mendoza found that the resistance to 10-1074 occurred more rapidly than 3BNC117, possibly because their half-lives differed. It led to periods of treatment where only one bNab was effective. They also found that the rebounding viruses had less genetic diversity. In the future, scientists want to adjust the antibody dosage so the half-lives of the bNabs correspond.

Bar-On’s also analyzed the effect of combining the two antibodies but did so on seven people who had not received ART treatment. Viral rebound occurred after 86 days, 60 days longer than if only one bNab was used. However, suppression only occurred in patients who had lower levels of virus to begin with. Additionally, some patients already had partial or complete resistance to one of the antibodies before the trial began.

Because of this resistance, using just antibodies to combat HIV may not be enough. However, a cocktail of antibodies could be a temporary replacement for ART, which can lessen the harmful side effects of ART and give their bodies some time to recover.

 

Photo Credits: BruceBlausHIV.png. November 12 2015. Blausen Medical Communications, Inc. Retrieved Dec. 2 2018 from https://upload.wikimedia.org/wikipedia/commons/e/ea/HIV.png

References:

Haigwood, Nancy L. “Antibodies Pose a Double Threat to HIV.” Nature, Springer Nature, 26 Sept. 2018, www.nature.com/articles/d41586-018-06773-8.

Bar-On, Yotam, et al. “Safety and Antiviral Activity of Combination HIV-1 Broadly Neutralizing Antibodies in Viremic Individuals.” Nature Medicine, Springer Nature, 26 Sept. 2018, www.nature.com/articles/s41591-018-0186-4#auth-1.

Mendoza, Pilar, et al. “Combination Therapy with Anti-HIV-1 Antibodies Maintains Viral Suppression.” Nature, Springer Nature, 26 Sept. 2018, www.nature.com/articles/s41586-018-0531-2.

“HIV Medicines and Side Effects Understanding HIV/AIDS.” AIDSinfo, U.S. Department of Health and Human Services, 29 Aug. 2018, aidsinfo.nih.gov/understanding-hiv-aids/fact-sheets/22/63/hiv-medicines-and-side-effects.