A New Home for HIV

UNC Researchers Discover Another Cell HIV Can Infect
May 10, 2016 

HIV is not the death sentence it used to be. In the 1990s more than 40,000 people could die because of HIV/AIDS in a single year. In 2013, that number had dropped to just fewer than 7,000 per year thanks to education and treatments that can manage the HIV virus.

“Manage” is the operative word, because even though modern medicines allow people with HIV to live long, healthy lives, there is still no cure for HIV. No matter how hard you hit it, the virus retreats to its hiding place—what scientists call its “reservoir”—where it waits in very small numbers until the coast is clear and it can come out again.

Without knowing where the reservoirs are, there’s no way to get in and attack HIV while it’s hiding. There are about 200 different types of cells in the human body and the virus could conceivably hide in any or all of them.

Macrophage Eating Another CellNow scientists in the Division of Infectious Diseases at the UNC School of Medicine have found at least one type of cell where HIV has a reservoir: the macrophage.

HIV is famous for attacking T-lymphocytes or T-cells. T-cells are the movers and shakers of our immune systems. They help other immune cells grow up, killing off cells infected by virus or cancer cells, and recognizing harmful proteins that our bodies have seen before and mounting the defense to stop them. 

Macrophages on the other hand are basically the Pac-Man of the immune system. They run around the blood stream and through all tissues devouring and digesting molecular trash and foreign invaders. Macrophage is Greek for “big eater.”

Dr. Jenna Honeycutt, a post-doctoral researcher at UNC, and her colleagues used humanized mice—mice that have been genetically engineered to have human immune cells instead of mouse cells—to show that the macrophages can support the HIV virus.

They created a strain of mice that had no T-cells, just immune cells in the macrophage family, and injected them with the HIV virus. They found HIV-infected macrophages in tissues throughout the mice’s bodies and recovered an HIV virus capable of replicating from these cells.

They even found that mice with infected macrophages, but no T-cells, were able to transmit the virus to other mice. So HIV can not only survive in these secondary cells, it can thrive and spread.

The reason this is so important is due to the way HIV generally works and how doctors currently treat it. What HIV does is infiltrate the T-cells, write virus DNA, splice the virus DNA into HIV on a T-Cellthe T-cells and then force the T-cells to produce more virus until they die. AIDS is what happens when too many T-cells die off and the body can no longer fight infections.

Current therapies for HIV involve interfering HIV’s functions in the T-cells. Antiretroviral therapy (ART) is a cocktail of different drugs that interfere with different things. One might keep HIV from getting into the T-cell, one might stop it from writing virus DNA, one might stop it from putting that DNA into the T-cell and the logic is that with all of these hurdles, the HIV virus is bound to trip somewhere.

For the most part, that works very well. Virus levels plummet down to a level where HIV has to lay dormant in its reservoir, from which it can’t emerge as long as the drugs are there to stop it.

But there is an issue here. Antiretroviral therapies are designed to stop HIV from doing its job in the T-cell. Cell types, however, are like car models, they all have more or less the same machinery in more or less the same place but every car does it just a little bit differently.

So let’s say a T-cell is 2014 Subaru Impreza hatchback and HIV gets into these cell-cars through the driver’s door. On a ’14 Impreza the door handles are the horizontal bars you wrap your fingers around and pull outward to open the door. Knowing this, you design a drug that recognizes when HIV wraps its hand around the handle and prevents it from pulling back to open the door. Success! You’ve kept HIV out of the car!

Now let’s say a macrophage is a 1992 Buick LeSabre sedan. The door handles on this one are also horizontal bars, but instead of pulling them back, there is a button you push with your thumb to open the door. Now your drug that worked on the T-cell sees HIV grabbing the macrophage door handle, it attaches and waits for the HIV to pull, but it doesn’t pull. It pushes and now HIV gets into car even though your drug was there to stop it.

HIV on a T-CellOn the other hand, some drugs can work on both cell types. Both the LeSabre and the Impreza start by turning a key. A drug that can wait in the car and stop a virus from making that key-turn motion would work on both types.

The real problem is that the researchers don’t have a good sense of what current medicines will work on a macrophage and what medicines won’t, so the group’s next study will test ART on the macrophage mice to see what effect it has. If there are shortfalls, at least researchers will know where to look to build new ART drugs.

“If the T-cells were the only target of HIV cure research, eradicating the virus would still be tough,” said UNC professor of medicine J. Victor Garcia, co-author of the study. “Now we have demonstrated that there is another cell target where replicating HIV can be found, which could make eradicating the virus from the host and finding a cure for HIV/AIDS harder.”

Garcia, who also studies ways to activate latent HIV so it can be killed, is referring to the challenge researchers already face in eradicating the virus from one type of cell without destroying the immune system. Adding macrophages to the list of cells that need to be cleared only complicates the process.

Still, having a more complete picture of where HIV works and where it goes to hide is a major step forward in finding a cure. Scientists now have a better idea of the question, they just need to work on an answer.

—Daniel Lane

Daniel Lane covers science, medicine, engineering and the environment in North Carolina.

 
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