HIV strains in India resist some top broadly neutralising antibodies

In 1994, a landmark paper in Science reported the isolation of an antibody called b12from an HIV-infected individual. The study showed that while pooled plasma containing billions of antibodies from HIV patients could neutralise viruses isolated from only 3 of 12 patients, b12 alone achieved similar neutralisation in 8 of the 12, and that, with one-fifth the amount of antibody present in the pooled plasma.

Soon, other antibodies with similar properties were identified that were capable of neutralising a wide range of HIV variants at remarkably low concentrations. This was an exciting development, as researchers were beginning to realise that conventional antibodies, which are normally among the immune system’s most powerful defences, are largely ineffective against HIV. These new antibodies, called broadly neutralising antibodies (bNAbs), raised hopes that they might one day help bring an end to the pandemic.

Since then, hundreds of bNAbs have been identified from different HIV-infected individuals. But despite early excitement, several challenges kept them from becoming the long-sought “magic bullet” that could end HIV. One major problem is the staggering genetic variation demonstrated by HIV. Even within a single patient, countless viral variants coexist, making it virtually impossible for any single bNAb to neutralise every virus. This means that even if someone naturally produces a bNAb, escape variants will persist and keep the infection alive.

Combinations of bNabs

One could potentially counter this by administering combinations of bNAbs, thus reducing the chances of viral escape. However, HIV has another trick up its sleeve. Once inside a cell, it can remain silent without producing new virus particles and thus evade immune detection. At any given moment, millions of cells may be in this silent state, while others actively produce viruses. Because bNAbs can only neutralise virus particles released from infected cells, the silent reservoir remains untouched. Clearing it would require maintaining the bNAb antibody cocktail treatment until every silent cell eventually reactivates — a process that has been predicted to take several decades.

One possible workaround is to train the body to make multiple bNAbs on its own. However, only a small fraction of people with HIV ever develop them. This limitation notwithstanding, vaccine researchers are working to induce the production of bNAbs by vaccination. Conventional antibodies, by definition, target specific regions on a pathogen; they usually fail against HIV because of the virus’s extreme variability. bNAbs are special because they recognise conserved regions of the viral envelope. These are sites that the virus cannot afford to change without compromising its survival. For example, one such location is the site that the virus uses to bind to CD4 receptors on the T-cells for infection. Mutations in this CD4 binding site would render the virus incapable of infecting hosts.

For several years, scientists have been testing combinations of bNAbs to see which ones can best neutralise the many strains of HIV found around the world. HIV can be classified into ‘subtypes’, which are similar but not identical variants of the virus. Each subtype has innumerable strains that circulate. No single bNAb can block all of them. Even within the same subtype, strains can differ in how sensitive they are. 

A recent paper published in the Journal of Virology by a team of researchers led by Jayanta Bhattacharya of the Translational Health Science & Technology Institute, Faridabad, has now shown that bNAb effectiveness can also differ between viruses of the same subtype circulating in different geographical regions.

The study, funded by the Team Science Grant of the DBT/Wellcome Trust India Alliance, compared the ability of 14 of the best bNAbs in the world to neutralise contemporary HIV variants circulating in India and South Africa.

The researchers found that Indian strains of HIV were most effectively neutralised by broadly neutralizing antibodies (bNAbs) that target a region on the viral surface known as the V3 glycan. Antibodies directed against the CD4 binding site also showed good activity, though somewhat less so. In contrast, antibodies aimed at the V1/V2 apex of the viral spike protein were far less effective, with most Indian strains showing strong resistance to this class. An intriguing pattern also emerged: viruses that resisted neutralisation by V1/V2-apex antibodies were often well controlled by CD4-binding-site antibodies.

Building on these observations, the team proposed a novel cocktail of three bNAbs called BG18, N6, and PGDM1400, that they predict to be able to neutralise a large proportion of circulating Indian HIV-1 strains with high efficiency. Such rational combinations could help overcome the virus’s ability to evade individual antibodies.

Important lesson

The study also uncovered striking regional differences. When viruses from India were compared with those from South Africa, the researchers found that Indian strains were more sensitive to antibodies such as N6, 10-1074, and BG18, but slightly more resistant to CAP256-VRC26.25. According to Prof. Bhattacharya, these differences likely arise from subtle changes in the viral spike protein, particularly in the structural motifs that form the antibody binding sites. These altered motifs can determine whether a particular antibody will be effective.

He also emphasised that the results of the study open up important opportunities for region-specific HIV prevention strategies, such as passive immunisation of high-risk individuals with carefully chosen antibody cocktails, or the design of vaccines that elicit similarly broad and potent antibody responses. He also highlighted the need for ongoing surveillance of both viral diversity and antibody effectiveness to ensure the most promising antibody combinations are prioritized for clinical development.

Overall, the study highlights an important lesson for HIV researchers worldwide. Because HIV’s remarkable genetic diversity allows it to evolve differently in different parts of the world, novel treatments and vaccines may not work everywhere in the same way. As Prof. Bhattacharya pointed out, regional studies like this one are essential to design therapies that are truly effective on a global scale.

Arun Panchapakesan is an assistant professor at the Y.R. Gaitonde Centre for AIDS Research and Education, Chennai.