HIV can change to evade an antibody, but escaping may come at a cost

A South African-United States study has uncovered how HIV can evolve to resist an antibody designed to prevent infection, offering clues for developing stronger antibody-based prevention strategies.

Imagine a key designed to fit a lock. Change the shape of the lock, and the key may no longer work. HIV can do something similar. The virus can change the part of its surface that an antibody recognises, making it harder for the antibody to block infection. But these changes may also come at a cost to the virus itself.

In a study published in Nature Microbiology, researchers investigated how HIV evolved after people acquired the virus despite receiving VRC01, a broadly neutralising antibody designed to block HIV from entering human cells.

The international study was led by Professor Carolyn Williamson, a virologist at the University of Cape Town’s (UCT) Institute of Infectious Disease and Molecular Medicine (IDM) and the National Health Laboratory Service, alongside researchers from the University of the Witwatersrand (Wits) and international partner institutions.

An unexpected escape route

VRC01 was tested in large international HIV antibody-mediated prevention (AMP) trials involving more than 4 600 participants. Although it provided about 75% protection against viruses highly sensitive to the antibody, it did not prevent HIV infections overall.

To understand what happened when infection occurred, researchers analysed 11 730 HIV genetic sequences from 47 trial participants.

Among the 26 participants who had received VRC01, eight developed new mutations associated with resistance. No such mutations were detected in the 21 participants who received a placebo.

Professor Williamson had expected HIV to find it difficult to escape an antibody targeting a part of the virus essential for entering human cells.

“I didn’t think it would be as high as 31%,” she said.

The AMP trial underestimated the dose of antibody needed to block HIV acquisition, providing a window of opportunity for the virus to escape.

Could resistance be a weakness?

There was another intriguing finding. The mutations identified in the study were rare among HIV viruses circulating globally. This raises the possibility that changes helping HIV evade an antibody may also make the virus less able to thrive, although researchers have yet to establish whether this is the case.

If resistance comes at a biological cost, that could help scientists design combinations of antibodies that are harder for HIV to evade.

“Maybe at some point the virus runs out of evolutionary options to be able to escape.”

The researchers also found that newer antibodies, including N6 and 1-18, largely retained their ability to neutralise viruses that had escaped VRC01.

“If you put combinations of antibodies together in the future and each of them can be escaped, but only at a cost, then maybe at some point the virus runs out of evolutionary options to be able to escape,” said Professor Penny Moore of Wits’ Antibody Immunity Research Unit.

This offers encouragement for developing more potent prevention approaches that target HIV in different ways.

Finding what might otherwise be missed

The team used deep sequencing to examine thousands of viral genetic sequences, allowing them to detect changes that might have been missed by conventional methods. HIV exists as a changing population of related viruses, rather than one identical virus. Deep sequencing helps researchers spot rare variants within that population and understand how the virus responds to pressure from an antibody.

The findings highlight the importance of advanced sequencing research in South Africa and provide insights that could help guide the development of future HIV prevention strategies and vaccines.

HIV can adapt to a single line of defence. Understanding how it does so and whether that adaptation weakens the virus could help researchers build stronger vaccine candidates.

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