HIV has a nasty habit of lying dormant in certain populations of cells, invisible to the immune system and to any drugs we try and attack it with. Purging these so called “reservoirs” and then destroying them is widely regarded as the prerequisite for a long-awaited cure, and new research suggests we might be getting close. Scientists from the National Institute of Allergy and Infectious Diseases have created a novel antibody that not only wakes up sleeping HIV, but also sends the immune system after the cells containing these previously hidden pools of virus.
For a single antibody to achieve a two-pronged attack is impressive, and it was achieved, perhaps unsurprisingly, by giving it dual specificity – basically the ability to recognize two different things. More specifically, they made the antibody in such a way that it could both activate white blood cells containing dormant, or latent, HIV, and then prompt their destruction through a process called lysis, whereby the cell membrane gets broken down and the contents fatally spill out.
As described in Nature Communications, they did this by firstly directing the antibody towards a spiky part of the HIV particle called the envelope, which serves to stick the virus to target cells and thus facilitate entry. This structure kind of looks like a lollipop stuck through an orange, with the head of the lolly making initial contact with cells, or more specifically a receptor found on white blood cells called CD4. Because this is such a crucial stage in the virus life cycle, the binding site is highly conserved, or displays little variation among viruses. Targeting it therefore means antibodies have a broad range of activity, rather than only being effective against a few strains of the virus.
The second target they went for was a cellular surface protein called CD3, which forms part of a crucial receptor found on a type of white blood cells called a T cell – one of HIV’s main targets. What this unique combination did was first activate the latently infected cell by engaging with CD3, which prompted the virus to start actively replicating. Then, as new envelope proteins are churned out, these are recognized by the other part of the antibody, which then flags up the cell to the immune system for subsequent lysis.
So in sum, the virus gets jolted awake, dropping its invisibility cloak and thus becoming vulnerable to detection not only by drugs but also by the immune system, which comes along and destroys the cell in which it is residing. The ultimate hope is that this could get rid of much of the problematic viral reservoirs in the body, bringing us a step closer to a cure.
All of this sounds great in theory, but whether it works effectively in humans remains to be seen. That said, the antibody has proven to be safe in non-human primates, so things are looking good for further trials which will investigate its efficacy in animal models, before hopefully moving on to human studies.