A computational approach could help clinicians select the best combinations of broadly neutralizing antibodies to treat HIV based on the genetics of the virus

Carefully designed cocktails of broadly neutralizing antibodies (bNAbs) could help treat HIV while minimizing the risk of the virus escaping treatment, suggests a study published today in eLife.

The study shows that computational approaches to select bNAb combinations based on viral genetics could help prevent viral evasion, making HIV treatment more effective. It may also offer a strategy for designing effective combinations of bNAbs to treat other rapidly evolving pathogens.

bNAbs offer a promising new tool to treat or potentially cure infections with rapidly evolving viruses such as HIV. Clinical trials using a single bNAb to treat HIV have shown that certain 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,” says Colin LaMont, a researcher at the Max Planck Institute for Dynamics and Self- organization in Göttingen, Germany.

LaMont and his colleagues used high-throughput sequencing to analyze the genetics of HIV viruses collected over 10 years from 11 untreated HIV patients. The team used this data to predict which viral strains might evade treatment with different bNAbs and whether bNAb evasion was associated with a cost of survival. Then, using computational methods, they applied the insights gained to predict viral rebounds in three real trials of bNAbs.

Finally, the team used their computational approach to find a combination of bNAbs that is least likely to allow any viruses to escape. They also found that certain bNAbs, such as 10-1074, are better against various virus populations because mutations that allow viruses to escape also make the virus less likely to survive. Others, including PGT121, are more effective against less diverse viral populations because escape mutations are rare. Overall, the results suggest that the optimal combination includes three bNAbs: PG9, PGT151 and VRC01.

“We have shown that the combination of PG9, PGT151 and VRC01 reduces the risk of viral rebound to less than 1%,” says LaMont. “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 (ART) that require daily doses could further improve long-term HIV treatment success,” suggests lead author Armita Nourmohammad, Assistant Professor in the Department of Physics at the University. of Washington, Seattle.

ART 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 more studies are needed to confirm the potential benefits of combining ART and bNAbs.

“Our study shows that exploiting genetic data can help us design more effective therapies against HIV,” concludes Nourmohammad. “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.”

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Irene B. Bowles