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Research will see if antibodies can more selectively target & kill HIV-infected cells

, by Emily Newman

antibodyEarly in January, Gilead Sciences announced an astounding $22 million HIV cure grants program benefitting 12 research teams around the world. The projects supported range in scope from basic science research to ethical and community-based social science research.

Galit Alter, PhD, a researcher at the Ragon Institute of MGH, MIT and Harvard and her team were one recipient of Gilead’s funding. Over the next three years, they will be developing a portfolio of broadly functional antibodies and testing them to see if they’re able to help eradicate cells that are latently infected with HIV from the body. Alter spoke with BETA to answer some questions about her research—and explain why she’s hopeful that an antibody-based cure therapy may prove to be both effective and realistic.

What is an antibody? Antibodies are proteins that our immune systems produce that help us fight viruses, toxins and other foreign substances in our body. Read more in this guide developed by Project Inform.

BETA: Thank you for taking the time to explain your research, Dr. Alter! We’re excited to hear more about how antibodies may contribute to an HIV cure. We’ve heard about broadly neutralizing antibodies before, but not broadly functional antibodies. Could you first explain what a broadly functional antibody is?

Galit Alter

Galit Alter, PhD (Photo: Ragon Institute)

Dr. Alter: Absolutely. The first thing to know is how antibodies work. Antibodies are Y-shaped molecules. The top of the Y—the two floppy arms—are the regions of antibodies that are involved in recognizing targets of interest (viruses, for example). Those ends of antibodies can block virus from getting into cells—that process is called neutralization. Broadly neutralizing antibodies are antibodies that block infection by attaching to the surface of viral cells.

We have this fantastic portfolio of neutralizing antibodies that are selected for their ability to bind and neutralize viruses. But, the targets of latently-infected cells may be different than the targets that are present on the surface of a virus. Which means that broadly neutralizing antibodies do not “recognize” cells that are latently infected with HIV [cells that contain viral DNA and may produce new virus in the future].

The other end of antibodies—at the bottom of the ‘Y’—is the domain of the antibody that provides function. It direct the innate immune system to kill. Broadly functional antibodies—what our team will be developing—are antibodies that not only can recognize latently infected cells, but then tell the immune cells to kill these cells off.

It sounds like the broadly functional antibodies you develop will then, if they work, help reduce or eliminate the “viral reservoir.” Is that right?

Yes. We’ll be making a whole new class of antibodies that will be directed at different epitopes [sites] on the surface of infected cells. We’re going to modify them to make them recruit these innate immune cells that are present within viral sanctuaries.

What is the viral reservoir?

Watch a short video that explains what latently-infected cells are, and why stand in the way of an HIV cure.

The goal of our particular proposal is to maximize all of the information we already have from infected people, as well as non-human primate models. We’ve really been able to find out where the virus hides within tissues. And now we’re going to be able to make rational antibody therapies that target in a very effective way and destroy latently-infected cells as quickly as possible.

What are the advantages to using antibodies as part of a potential cure strategy?

Specificity is the main goal here. A lot of approaches—such as ones that use chemicals or gene therapy—end up blocking the virus in a general way. With broadly functional antibodies, we may be able to target latently-infected cells in a very specific way.

If this were to be part of a therapy that’s tested and used in people, what would that look like?

Infusions are the most common way to deliver antibody therapy to people right now. But in the future, that might change. One day it might not be an infusion but it would just be a tiny injection of DNA that would populate the immune system with the antibody of interest.

Also, these antibodies are never going to be one-drug miracles. They will probably have to work with a latency-reversing agent, which is something that “pulls” HIV out of reservoir cells. In order for an antibody to be effective, the virus sort of has to expose itself on the surface of a reactivated cell. We’re going to work our hardest to make antibodies that are going to see the virus in ways that are specific to infected cells. But ultimately our therapeutic will only be efficacious once we start combining these with latency-reversing drugs.

Are you already thinking ahead to testing therapies in clinical trials with human participants?

Absolutely. That probably won’t be in the first three years. At the end of this grant period, our goal is essentially to make a couple of these monoclonal antibodies with the right modifications and to test them in monkey models.

But there is so much safety data out there for monoclonal antibodies, you can accelerate and move faster than you can with other kinds of drugs.

Many people in our audience wonder about seeing an HIV cure happen in their lifetime or in the near(ish) future. Do you have any insights you’d like to share?

The idea that we can make antibodies that will be able to see infected cells—for what they express and not assuming that they’re the same as the actual virus—is a testable hypothesis. It’s something we can have faith in.

There’s so much preparatory work that’s been done in the cancer field that’s identified how to make these antibodies more functional, to see how safe these things are in people, that I think it will lead to something, hopefully in the next three to five years, to really prove or disprove that this could be the foundation of cure. I’m hopeful. I wouldn’t have written the grant if I didn’t think it was possible.

 

 

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