HIV finds escape routes from preventive antibody – but newer antibodies may close them
- Wits University
A South African–US study reveals how HIV developed resistance after breakthrough infections in a landmark antibody-prevention trial.
Getting the correct dosage is critical for the next generation of HIV prevention
In a landmark HIV prevention trial, an antibody blocked viruses most vulnerable to it, but others broke through. Now researchers have uncovered how HIV evolved after those infections – and why the amount of antibody in the body is an essential part of the story.
The Antibody-Mediated Prevention (AMP) trials enrolled more than 4,600 volunteers across Africa, the Americas, and Europe to test VRC01, a laboratory-made broadly neutralising antibody (bnAb). Such antibodies can block many different strains of HIV and, unlike a vaccine, can be given directly rather than relying on the body to produce them.
In the AMP trial, VRC01 did not significantly reduce HIV infections overall, although it reduced infections caused by highly sensitive strains by about 75%. This study showed that HIV requires high antibody titers, and it illustrates the importance of maintaining those titers throughout the dosing cycle.
“We underestimated the dose of antibody required to be effective in vivo” said Professor Larry Corey of Fred Hutch Cancer Center, a lead investigator of AMP.
In other words, there were extended periods when antibody levels were too low to block less-sensitive viruses, creating opportunities for escape.
A new study published in Nature Microbiology has now examined what happened after infection in people who received VRC01. The findings show how a virus can respond to antibody pressure – and offer clues for improving future antibodies and vaccines.
An unexpected high frequency of escape
The researchers analysed 11,730 HIV envelope sequences from 47 selected AMP participants who acquired HIV with viruses initially susceptible to VRC01. New escape mutations emerged in eight of the 26 VRC01 recipients studied – 31% – but in none of the 21 placebo recipients.
Professor Carolyn Williamson, a virologist at the University of Cape Town's Institute of Infectious Disease and Molecular Medicine and the National Health Laboratory Service, had expected resistance to be harder to achieve as VRC01 attaches to the part of HIV that binds to a receptor on human immune cells, a step the virus needs to enter those cells. Yet a single genetic change was enough to make HIV resistant.
Professor Penny Moore of Wits University's Antibody Immunity Research Unit said the viruses frequently found different ways around VRC01. The results highlight “how malleable the virus is” even when an antibody targets such a critical region.
Rare mutations may come at a cost
There is an important difference between how often escape occurred in the study and how common those particular mutations are worldwide. Although eight participants developed escape variants, most of the genetic changes involved appear in fewer than 1% of circulating HIV sequences.
That rarity suggests resistance might come at a cost to HIV's ability to survive or compete. But this remains a possibility, not a proven finding. Researchers still need to learn whether the resistant viruses persist once antibody pressure disappears or change back to a more successful form.
“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,” Moore said.
Finding changes other methods would miss
The study was possible because scientists used deep sequencing to examine large numbers of viruses from each person. HIV exists within an individual as a shifting population of related viruses, so changes in a tiny minority can easily be overlooked.
“Deep sequencing found escape variants that sometimes made up only a small fraction of that viral population – variants conventional sequencing would have missed,” said Professor James Mullins of the University of Washington, a senior author of the paper.
The sequencing methods drew on work by Williamson's and Mullins's laboratories. Moore stressed the importance of maintaining this expertise in South Africa, not only for HIV but for investigating other pathogens.
“These are the kind of platforms that have to be retained if we're going to be able to answer questions about our own viruses,” she said.
Better antibodies, better protection
VRC01 is now an older-generation antibody. The researchers also tested whether viruses that escaped it could resist newer antibodies. Some mutations reduced sensitivity to other antibodies aimed at the same site, but more potent antibodies, including N6 and 1–18, largely remained effective.
“We have much better tools for sequencing the virus, but also much better tools for combating the virus,” Moore said.
The results suggest we should test more potent antibody concentrations and combinations that attack HIV in different ways, making it harder for the virus to develop resistance. The same lesson is relevant to HIV vaccines: researchers want to prompt the immune system to make antibodies against several vulnerable parts of the virus, rather than only one.
The study emerged from the international AMP trials and the HIV Vaccine Trials Network. It brings together South African researchers and trial sites with partners including Fred Hutch Cancer Center, the University of Washington and other US institutions. The samples collected to test whether VRC01 could prevent infection are still helping scientists work out how to make antibody-based prevention more durable.