AIDS Vaccine Research: Better By Design?

OD-GT8 60mer

Caption: eOD-GT8 60mer nanoparticle based on the engineered protein eOD-GT8. Yellow shows where eOD-GT8 binds antibodies; white is the protein surface outside the binding site; light blue indicates the sugars attached to the protein; dark blue is the nanoparticle core to which eOD-GT8 has been fused.
Credit: Sergey Menis and William Schief, The Scripps Research Institute

A while ago, I highlighted a promising new approach for designing a vaccine against the human immunodeficiency virus (HIV), the cause of AIDS. This strategy would “take the immune system to school” and teach it a series of lessons using several vaccine injections—each consisting of a different HIV proteins designed to push the immune system, step by step, toward the production of protective antibodies capable of fending off virtually all HIV strains. But a big unanswered question was whether most people actually possess the specific type of precursor immune cells that that can be taught to produce antibodies that kill HIV.

Now, we may have the answer [1]. In a study published in the journal Science, a research team, partly supported by NIH, found that the majority of people do indeed have these precursor cells. While the total number of these cells in each person may be low, this may be all that’s needed for the immune system to recognize a vaccine. Based in part on these findings, researchers plan to launch a Phase 1 clinical trial in human volunteers to see if their latest engineered protein can find these precursor cells and begin coaxing them through the complicated process of producing protective antibodies.

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Toward an AIDS-Free Generation: Can Antibodies Help?

Virus and antibody bound to virus

Caption: Left: Human Immunodeficiency Virus (HIV); Right: VRC01 antibody (blue and green) binding to HIV (grey and red). The VRC01-HIV binding (red) takes place where the virus attaches to primary immune cells.
Credits: C. Bickel, Science Translational Medicine; National Institute of Allergy and Infectious Diseases

This year, an estimated 50,000 Americans will learn they have been newly infected with the human immunodeficiency virus (HIV), which causes AIDS [1]. The good news is that if these people are diagnosed and receive antiretroviral therapy (ART) promptly, most will enjoy a near-normal lifespan.The bad news is that, barring any further research advances, they will have to take ART every day for the rest of their lives, a regimen that’s inconvenient and may cause unpleasant side effects. Clearly, a new generation of safe, effective, and longer-lasting treatments to keep HIV in check is very much needed.

That’s why I’m encouraged to see some early signs of progress emerging from a small, NIH-supported clinical trial of an HIV-neutralizing antibody. While the results need to be replicated in much larger studies, researchers discovered that a single infusion of the antibody reduced levels of HIV in the bloodstreams of several HIV-infected individuals by more than 10-fold [2]. Furthermore, the study found that this antibody—known as a broadly neutralizing antibody (bNAb) for its ability to defend against a wide range of HIV strains—is well tolerated and remained in the participants’ bloodstreams for weeks.

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Happy New Year … and a Look Back at a Memorable 2015

Four NIH-supported science breakthroughs for 2015A new year has arrived, and it’s going to be an amazing one for biomedical research. But before diving into our first “new science” post of 2016, let’s take a quick look back at 2015 and some of its remarkable accomplishments. A great place to reflect on “the year that was” is the journal Science’s annual Top 10 list of advances in all of scientific research worldwide. Four of 2015’s Top 10 featured developments directly benefited from NIH support—including Science’s “Breakthrough of the Year,” the CRISPR/Cas9 gene-editing technique. Here’s a little more on the NIH-assisted breakthroughs:

CRISPR Makes the Cut: I’ve highlighted CRISPR/Cas9 in several posts. This gene-editing system consists of a short segment of RNA that is attached to an enzyme. The RNA is preprogrammed to find a distinct short sequence of DNA and deliver the enzyme, which acts like a scalpel to slice the sequence out of the genome. It’s fast and pretty precise. Although CRISPR/Cas9 isn’t brand-new—it’s been under development as a gene-editing tool for a few years—Science considered 2015 to be “the year that it broke away from the pack.”

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Snapshots of Life: Host vs. Pathogen

Cryptoccocus neoformans

Caption: This scanning electron microscopy image shows mouse macrophages (green) interacting with a fungal cell (blue).
Credit: Sabriya Stukes and Hillary Guzik, Albert Einstein College of Medicine

Macrophages are white blood cells that generally destroy foreign invaders by engulfing them. It’s a tried-and-true strategy, but it doesn’t always work. Cryptoccocus neoformans, a deadly fungal pathogen commonly found in the feces of pigeons, can foil even the best macrophages. No one has captured this grand escape—but researchers are getting a whole lot closer to doing so.

Sabriya Stukes, an NIH-funded microbiologist at New York’s Albert Einstein College of Medicine, studies the interactions between C. neoformans and macrophages to determine how the former causes the lung infection cryptococcosis, which can be deadly for people with compromised immune systems. Stukes believes what makes C. neoformans so dangerous is that it can survive the acid death chamber inside macrophages—a situation that spells doom for most other pathogens. A big reason behind this fungus’s power of survival is its thick coat of polysaccharides, which serves as woolly-looking armor. Once a macrophage engulfs the fungus, this coat can give the white blood cell “indigestion,” prompting it to spit the fungus back into the lungs where it can cause disease.  Continue reading

Vaccine Research: New Tactics for Tackling HIV

HIV-infected Immune Cell

Caption: Scanning electron micrograph of an HIV-infected immune cell.
Credit: National Institute of Allergy and Infectious Diseases, NIH

For many of the viruses that make people sick—think measles, smallpox, or polio—vaccines that deliver weakened or killed virus encourage the immune system to produce antibodies that afford near complete protection in the event of an exposure. But that simple and straightforward approach doesn’t work in the case of human immunodeficiency virus (HIV), the virus that causes AIDS. In part, that’s because our immune system is poorly equipped to recognize HIV and mount an attack against the infection. To make matters worse, HIV has a habit of quickly mutating as it multiplies.That means, in order for an HIV vaccine to be effective, it must induce antibodies capable of fighting against a wide range of HIV strains. For all these reasons, the three decades of effort to develop an HIV vaccine have turned out to be enormously challenging and frustrating.

But now I’m pleased to report that NIH-funded scientists have taken some encouraging strides down this path. In two papers published in Science [1, 2] and one in Cell [3], researchers presented results of animal studies that support what most vaccine experts have come to suspect: the immune system is in fact capable of producing the kind of antibodies that should be protective against HIV, but it takes more than one step to get there. In effect, a successful vaccine strategy has to “take the immune system to school,” and it requires more than one lesson to pass the final exam. Specifically, what’s needed seems to be a series of shots—each consisting of a different engineered protein designed to push the immune system, step by step, toward the production of protective antibodies that will work against virtually all HIV strains.

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