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A calculated risk: Evaluating HIV resistance to the broadly neutralising antibodies10-1074 and 3BNC117
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"......As bNAbs have only recently become available as a therapy, this would suggest that overlapping pressures from circulating antibodies may result in immune escape, which is potentially transmitted to new hosts resulting in an increase in population level resistance. Should this pattern continue at the current rate – or even accelerate – this may have future implications for the broader utility of bNAb therapy.
There is growing evidence that bNAbs, such as 10-1074 and 3BNC117, are an exciting new treatment option which may be used alone or in conjunction with antiretroviral treatment to confer long-term virological control. Their use in hard-to-reach groups and regions with poor healthcare infrastructure could deliver viral suppression to individuals where it is currently challenging. However, viral resistance to bNAbs could set back the success of the intervention and so developing tools to accurately predict bNAb sensitivity has become a point of focus in the field. In this review, we outlined the signatures associated with resistance in vivo and the available tools for predicting sensitivity to 10-1074 and 3BNC117.However, as this is such a new area, knowledge of the virological genotypic and phenotypic features that predict resistance is still limited. As more clinical bNAb trials enrol, and more data are collected on outcomes, it will hopefully become possible to develop the necessary more robust methodologies needed to help guide clinical decision-making."
Abstract
Purpose of this review
Broadly neutralising antibodies (bNAbs) are a promising new therapy for the treatment of HIV infection. However, the effective use of bNAbs is impacted by the presence of preexisting virological resistance and the potential to develop new resistance during treatment. With several bNAb clinical trials underway, sensitive and scalable assays are needed to screen for resistance. This review summarises the data on resistance from published clinical trials using the bNAbs 10-1074 and 3BNC117 and evaluates current approaches for detecting bNAb sensitivity as well as their limitations.
Recent findings
Analyses of samples from clinical trials of 10-1074 and 3BNC117 reveal viral mutations that emerge on therapy which may result in bNAb resistance. These mutations are also found in some potential study participants prior to bNAb exposure. These clinical data are further informed by ex-vivo neutralisation assays which offer an alternative measure of resistance and allow more detailed interrogation of specific viral mutations. However, the limited amount of publicly available data and the need for better understanding of other viral features that may affect bNAb binding mean there is no widely accepted approach to measuring bNAb resistance.
Summary
Resistance to the bNAbs 10-1074 and 3BNC117 may significantly impact clinical outcome following their therapeutic administration. Predicting bNAb resistance may help to lower the risk of treatment failure and therefore a robust methodology to screen for bNAb sensitivity is needed.
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