GUEST AUTHOR: Nick Kolev

A new study from the Balazs Lab at the Ragon Institute, published in Immunity, demonstrates that HIV escapes broadly neutralizing antibodies (bNAbs) through a limited set of conserved mutation paths, and that manipulating the cost of those paths can dramatically improve therapeutic outcomes.

Broadly neutralizing antibodies are among the most promising tools for treating and preventing HIV. Unlike conventional antiretroviral drugs, bNAbs target the virus’s surface directly and can block infection across many strains. But clinical trials have repeatedly shown that HIV can evolve resistance, undermining the antibodies’ effectiveness. Understanding how and why the virus escapes has remained a central challenge.

“Broadly neutralizing antibodies have been evaluated based on metrics like their average potency across diverse isolates and the breadth of their neutralizing ability, but we find that therapeutic efficacy in animals has more to do with the ability of HIV to escape” said principal investigator and corresponding author Alejandro Balazs, PhD. 

“By studying the mutations the virus makes during selection by these antibodies, we find that the ease or difficulty of escape paths available to the virus are the real drivers of success or failure during treatment,” he said. “We believe this insight will be crucial for the development of future HIV therapies that employ combinations of antibodies that can exert orthogonal selective pressure on the virus to produce the check-mate conditions needed to continuously suppress HIV as a functional cure”.

Using humanized mice and AAV vectors that allow a single injection to produce sustained antibody levels, the team tested three bNAbs against two clinically relevant HIV strains. Deep sequencing revealed that for each antibody, the virus consistently followed a small number of the same escape paths. Some of those paths came at little cost to the virus, allowing rapid resistance. Others carried a heavy fitness penalty, and in those cases the virus often failed to escape at all. One antibody, VRC07, suppressed HIV for 44% of subjects for the full six-month study by forcing the virus down a particularly costly route.

The team then showed they could shift the outcome in both directions. Swapping a small piece of the viral envelope between strains made escape easier, while introducing a polymerase mutation that reduced the virus’s overall fitness made escape harder, resulting in complete suppression.

The findings suggest that future antibody therapies should be evaluated not just on how broadly they neutralize HIV, but on how difficult they make it for the virus to escape.