The HIV Research for Prevention conference (HIVR4P 2018) in Madrid last week was dominated by studies of one type of molecule – broadly neutralising antibodies (bNAbs). These complex molecules, which develop in some people with HIV after years of infection, are natural entry inhibitors, stopping the virus from attaching to and infecting cells.
Many kinds of antibodies act as ‘red flags’ alerting other parts of the immune system to the presence of HIV, and tagging infected cells for destruction. But they cannot be used widely as treatments or for prevention, as they arise in response to very specific viruses and are quickly rendered ineffective by HIV’s high mutation rate, and also by the defensive shield of sticky molecules it uses to shield itself from immune attack.
Broadly neutralising antibodies, as their name suggests, have evolved to get through these defences and attack highly conserved parts of the virus – parts of its proteins that are important to its functioning and which it finds difficult to alter.
The HIVR4P conference heard about a large number of studies of bNAbs. They can be infused ‘passively’, i.e. made outside the body and given in drips as long-lasting drugs. If this sounds like cancer therapy, it is, as antibodies that seek out and destroy rogue cells have become the mainstay of new-generation cancer treatments.
The reason researchers are interested in bNAbs for HIV is not only because they could treat virus resistant to other kinds of drugs – which they could. Neither is it simply because a single infusion of antibodies can last weeks in the body – though it can, and bNAbs are therefore of interest as a kind of new-generation pre-exposure prophylaxis (PrEP).
It is also because of the way they alert other parts of the immune system, in processes called ADCC or ADCP (antibody-directed cell-mediated cytotoxicity or phagocytosis), whose effect can be maintained for long after they have disappeared from the body. There was further data at HIVR4P from a treatment study already published in September, which found that some people given a combination of two bNAbs were able to maintain undetectable viral loads for several months after the last dose of bNAbs without having to use conventional HIV drugs.
Most exciting is the possibility that – since they arise naturally in response to infection – a finely tuned vaccine could induce people to make their own bNAbs. In theory a bNAb-stimulating vaccine could prevent HIV infection altogether. Almost as good would be a therapeutic vaccine which, given after infection, could maintain such a high level of immune suppression that HIV infection goes into permanent remission.
Such possibilities are largely at the preclinical stage, with studies ‘reverse engineering’ bNAbs to find what pattern of genetic changes in the B-cells that make antibodies are needed in order for them to be produced (Shen). Another study (Thomas) performed the same reverse-engineering method to see what genes had to change in order for monkeys to develop protection against HIV in precursors to the RV144 vaccination trial, now used as the basis for the vaccine in one of the current HIV vaccine studies, Uhambo (HVTN 702).
However, the conference did hear about one study that used sophisticated gene therapy to induce monkeys to make their own bNAbs and produced an apparently functional cure in one monkey – see this report.