On the first World AIDS Day on Dec 1, 1988, a diagnosis of HIV was viewed as a death sentence. Nearly three decades later, many patients live with the disease thanks to anti-retroviral therapies (ART).
However, while many patients can now lead full lives thanks to ART, there is still no outright cure for the disease. People with HIV still live under the shadow of potentially lethal infections that could strike if they develop AIDS (Acquired Immune Deficiency Syndrome), the life-changing result of untreated HIV that depletes the immune system and leaves the body vulnerable to attack from pathogens it would normally fight off with ease.
Scientists now know that each HIV virus particle (called a virion) goes through a life cycle. The cycle is made up of steps which include infection, replication, assembly, budding and release.
At Emory University, Dr. Paul Spearman, MD, is looking to exploit that cycle, interrupting it at key points and stopping the virus dead in its tracks. He does this using the GE Healthcare Deltavision OMXTM microscope and GE Healthcare Life Science’s AKTATM Protein Purification Systems.
He is looking for ways to disrupt the process by which newly made virions come together before moving on to their next target. This way, he could make the cells non-infectious and stop the virus from replicating.
Before looking at how Dr. Spearman hopes to achieve this, here are some basics about HIV’s life cycle, and at which point in the cycle Dr. Spearman hopes to knock HIV out.
The HIV Life Cycle
Attachment – the HIV particle binds to a T-cell.
Fusion – an envelope made of protein around the HIV particle fuses with the cell, at which point HIV enters it.
Replication – the HIV particle hijacks the cell’s own replication mechanism by forcing it to create HIV DNA and integrate with the DNA of the T-cell. This forces the T-cell to make lots of HIV proteins, the building blocks for more HIV
Assembly – when the new HIV proteins assemble into new virions and move to the cell surface
Budding – the new virions push themselves out of the cell by making a new protein envelope around themselves and ‘budding off’ the cell surface. From there the virions infect other cells and replicate further.
“It is the last parts of the life cycle we’re looking at,” said Dr. Spearman. “That’s the exciting part to us. It’s defining the intricacies of that particular step, which we can then disrupt. Once we can manipulate that pathway, all the particles that are budding off from the cell l lack an envelope and are non-infectious. It’s a nice, targetable part of the assembly pathway as well, so we’re excited about that for the future.”
In order to see exactly what is going on in the HIV life cycle, Dr. Spearman uses the Deltavision OMXTM to observe live cells infected with HIV in unprecedented detail.
“We have nice evidence of disrupting envelope trafficking and stopping the spread of the virus,” Spearman says. “We have been using Deltavision for about seven years, and now we are learning new details of the assembly pathway using the OMX.”
He says once the pathway is fully understood, he can work on developing an inhibitor, be it in the form of a vaccine or a drug, that could precisely target the HIV envelope assembly pathway. “To really make an effective intervention, we would probably [need to use] a small molecule that would target the interaction between HIV and the protein envelope,” he added.
Talking about when this research could be translated into therapy, Dr. Spearman has high hopes, although it will take some time. “There are several steps before [clinical trials], realistically,” he said. “We need to define the interaction between HIV and cell surfaces. That interaction needs to be defined in a number of ways: biochemically, structurally, and we need to understand more about… how the pathway leads to successful incorporation of the HIV envelope in the cell at a very detailed level. So we’ve got work to do there!”
Leading up to World AIDS Day on December 1, The Pulse is taking a close look at the pioneering work of three leading scientists, pushing the boundaries of science to find a cure. Click here to learn about how Dr. Crowe is harnessing the power of people who can naturally ‘control’ their HIV, and how Dr. Hope is shedding light on HIV from every angle.