Why was a broadly neutralizing anti-HIV-1 antibody (3BNC117) tested at the start of antiretroviral therapy?
The standard treatment for HIV is antiretroviral therapy (ART). ART is extremely effective in supprissing HIV and can hold the disease in check, but viremia quickly reappears (within 2-4 weeks) if ART is paused. There are many good ART combinations to choose from, but ART does not cure HIV and therefore ART needs to be taken for the rest of a person’s life to avoid disease progression, excess morbidity and to avoid new transmission.
Previous clinical trials with experimental medicines have not shown any significant effects on the persons’ immunity towards to virus or the immune system’s ability to suppress virus if ART was paused.
bNAbs mediates their antiviral effects through different mechanisms than regular small molecule antiretroviral drugs such as ART. In addition to direct neutralization of viruses, bNAbs can also engage the immune system through their Fc domains and form antibody–antigen immune complexes - for the Fc-mediated functions to occur antigen needs to be present, which is the case with viremia at ART start.
Antigen–antibody complexes can form when bNAbs bind to viruses (figure 1A; below) or antigen on infected cells (figure 1B; below). These immune complexes stimulate the persons' immunity towards the virus.
FIGURE 1. (a) Illustration of the effects of broadly neutralizing antibodies (bNAbs) and latency reversing agents (LRA) in combination. bNAbs-antigen complexes bind to plasmacytoid dendritic cells (pDCs) via the Fcy receptors. This cross-presents viral antigens on the MHC class I molecule leading to development of HIV-1-specific CD8+ T cell and enhanced killing of infected cells. (b) Illustration of the effects of bNAbs and immune modulators such as TLR agonists in combination. TLR agonists prime the innate immune system through pDC activation. Primed innate immune cells (here a NK cell) bind the bNAbs via the Fcg receptors and mediate antibody-dependent cellular cytotoxicity (ADCC). (graphics: Gitte Skovgaard Jensen, AUH). https://journals.lww.com/10.1097/COH.0000000000000641
Why did the broadly neutralizing anti-HIV-1 antibody (3BNC117) boost the body’s own ability to suppress the virus?
Many clinical trials have tested HIV curative strategies but most failed to make any impact on the number of infected cells (known as the HIV reservoir) or on the immune system ability to control the virus. Enhancement of the persons' immunity towards the virus has not been observed among peolpe living with HIV suppressed on long-term ART who receive bNAbs in addition to ART. In our study, we tried to intervene right as people with newly diagnosed HIV infection were starting ART. This approach is very different from previous studies which have tested interventions among people living with HIV who have been on ART for many years (figure 2a; below).
The eCLEAR study.
But in our randomized study we showed that newly diagnosed people with HIV given broadly neutralizing anti-HIV-1 antibodies (bNAbs) together with ART had a faster decrease in the amount of virus in the blood after the ART start and develop better immunity against the virus, and their immune system can partially or completely suppress the virus if ART is paused. Importantly, the proportion of individuals who were capable of partially or completely controlling the virus were much higher among those who had sensitive viruses and received bNAbs, than the rest of the study participants (figre 3b; below).
This is important because many researchers believe that the immune system is the key to a cure for HIV based on real life examples where some rare individuals (elite controller and post-treatment controllers) have an immune system that can completely suppress the virus for many years without the need for ART.
Who was enrolled in the study?
Our study cohort was men and women with a new diagnosis of HIV infection living in Denmark and the UK.
What is the chief takeaways of the study?
That potent bNAbs might be a way to reduce the amount of virus beyond what can be achieved with standard of care ART and that these bNAbs also might improve the immune system’s ability to control the virus if ART is stopped.
Why is your conclusion important to help those with HIV?
This is a hopefully step in the right direction but much more work and improvement of the treatment strategy is needed before we might one day have a safe, scalable cure for HIV. In this study, we focused on people with newly diagnosed HIV but a high priority for future research should be to tests similar treatment strategies in those who have already been on ART for years.
What happens next?
New clinical trials are being planned to repeat these results but using an optimized longer-acting and broader combination of bNAbs in bigger trials both in Europe, the USA and Africa.