Scientists may have just made a giant leap forward in the ongoing battle against HIV with the development of a new candidate therapy that is so potent and widely effective against different strains of the virus, it could even serve as the basis for the design of a long sought-after vaccine.
As described in the journal Nature, scientists found that their novel construct blocked both types of HIV and also the non-human primate form, SIV, from getting into cells, and that this protection lasted for a minimum of eight months post-administration, but potentially years. According to the team, this is by far the broadest and most effective inhibitor of entry so far described.
In order to get inside target cells, which are predominantly a type of white blood cell called a T lymphocyte, HIV needs to first use its spiky surface proteins to latch onto a receptor called CD4. While this is a necessary first step, it’s not sufficient to gain entry, so the virus also has to grasp onto another anchoring point, called a coreceptor. There are actually two different coreceptors, CCR5 and CXCR4, but around 90% of newly transmitted HIV use the former.
Since viruses can’t replicate outside cells, many therapies seek to block this entry process, which can be achieved in a number of ways. Immune molecules, called broadly neutralizing antibodies, are of particular interest because they are effective against a wide range of viral strains. That’s because they target critical conserved regions of the virus, rather than bits that vary or that the virus can easily mutate, which reduces the risk of resistance rapidly developing. But unfortunately, even the most effective ones only neutralize (prevent from entering) about 10-50% of HIV-1, and they do so fairly inefficiently.
Another promising strategy is using an antibody-like molecule called an immunoadhesin, which can be designed to stick to parts of the virus that are used to get inside the cell. While they neutralize a range of viruses and are safe for use in humans, they are not particularly potent on their own. This led scientists from the Scripps Research Institute to wonder whether a combination of molecules that target both the CD4 and the coreceptor binding site of HIV simultaneously could be effective.
To test out this hypothesis, they used a modified, harmless virus as a vehicle to deliver two different genes to cells, one coding for a close mimic of CCR5 and the other an immunoadhesin form of CD4. Once inside these cells, much like with HIV, the virus turns the cell into a factory that churns out these protective proteins. These proteins then circulate round the body, ready to stick to the surface of HIV and thus prevent it from getting inside cells.
When they tested the therapy on cells in a dish, they found it neutralized 100% of a diverse pool of HIV-1, HIV-2 and SIV strains, even those that were neutralization-resistant. Furthermore, when administered to monkeys that are susceptible to SIV, they were protected from multiple challenges with the virus, and continued to produce the engineered proteins for at least eight months. However, other studies have suggested that production can continue for years, raising the possibility that this strategy could be used in the design of a universal HIV vaccine in humans.