New combination therapies for HIV could prevent viral leakage and rebound

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July 22, 2022

This image, taken with a scanning electron microscope, shows an HIV-infected human H9 T cell.National Institute of Allergy and Infectious Diseases

A study published July 19 in the journal eLife brings new hope for HIV treatments. Research by scientists from the University of Washington, the Max Planck Institute for Dynamics and Self-Organization, and the University of Cologne indicates that carefully crafted cocktails of broadly neutralizing antibodies, or bNAbs, could help treat HIV while minimizing the risk of the virus progressing. to “escape” treatment.

The study shows that computational approaches to select bNAb combinations based on viral genetics could help prevent viral evasion, making HIV treatment more effective.

“Our study shows that harnessing genetic data can help us design more effective HIV therapies,” said the lead author. Armita Nourmohammad, assistant professor of physics at UW. “Our approach may also be useful for designing therapies against other rapidly evolving disease-causing agents, such as the hepatitis C virus, drug-resistant bacteria, or cancerous tumor cells.”

Antibodies are a class of proteins made by the immune system to recognize and fight pathogens. In HIV infections, bNAbs are a specific subset of antibodies that recognize multiple strains of HIV.

Broadly neutralizing antibodies offer a promising new tool to treat or potentially cure infections with rapidly evolving viruses such as HIV. But clinical trials using a single bNAb to treat HIV have shown that some viral strains can survive treatment and cause viruses to rebound in the blood. Combinations of bNAbs may therefore be a more effective approach, but finding the best combinations is a challenge.

“For our study, we proposed to use a computational approach to predict the efficacy of bNAb combinations based on HIV genetics,” said lead author Colin LaMont, researcher at the Max Planck Institute for Dynamics. and self-organization in Germany.

The team used high-throughput DNA sequencing to analyze HIV virus genomes collected over 10 years from 11 untreated HIV-positive patients. They used this data to predict which viral strains might be able to evade treatment with different bNAbs and whether evolving to evade bNAbs was associated with a survival cost. Then, using computational methods, they applied the insights gained to predict viral rebounds in three real trials using bNAbs. Finally, the team used their computational approach to develop a combination of bNAbs that is least likely to allow any viruses to escape.

In the process, they uncovered the reasons why some bNAbs target broader HIV populations than others. For example, some bNAbs, like one called 10-1074, work better against various virus populations because mutations that allow viruses to escape from 10-1074 also make those viruses less likely to survive. Other bNAbs, including one called PGT121, are more effective against viral populations with low genetic diversity because mutations that allow escape are rare. Overall, the results suggest that the optimal combination includes three bNAbs: PG9, PGT151 and VRC01.

“We showed that the combination of PG9, PGT151 and VRC01 reduces the risk of viral rebound to less than 1%,” LaMont said. “It does this by targeting three different regions of the virus’ protective outer packaging, or envelope.”

“Combining bNAbs, given by intravenous infusion every few months, with current antiretroviral therapies that require daily doses could further improve long-term HIV treatment success,” Nourmohammad said.

Antiretroviral therapy reduces the ability of HIV to multiply and create new variants, limiting the genetic diversity of the viral population and reducing the likelihood of bNAb escape variants emerging. The authors say that future studies are needed to confirm the potential benefits of combining antiretroviral therapy and broadly neutralizing antibodies.

The study’s co-authors are Jakub Otwinowski from the Max Planck Institute for Dynamics and Self-Organization and Kanika Vanshylla, Henning Gruell and Florian Klein from the University of Cologne in Germany. The research was funded by the National Science Foundation, the German Research Foundation and the Max Planck Institute for Dynamics and Self-Organization.

For more information, contact Nourmohammad at [email protected].

Adapted from a Press release by eLife.

Tag(s): Armita Nourmohammad • Faculty of Arts and Sciences • Department of Physics • HIV and AIDS • Medicine and Pharmaceuticals • Population Health


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