T Cell as Trojan Horse: Insights into How HIV Eludes the Immune System

HIV, the virus that causes AIDS, has a talent for spreading between cells of the immune system. Through a process called budding, virus particles are released from an infected cell as little blobs that protrude outward and then pinch off from the cell membrane. Once released from the host cell, the virus particles are free to move to other cells and infect them.

This budding process is emblematic of HIV and other viruses that are surrounded by a membrane, or envelope. Each virus particle takes a bit of cell membrane with it when it departs. By slowly denuding the immune cell of its membrane, the virus kills its host cell. When enough immune cells die, the result is immunodeficiency, or AIDS.

For many years, it was believed that this budding process represented a new type of cellular behavior induced by the virus—as if (to use a modern analogy) your computer started sending emails without your permission. Now, researchers with NYU School of Medicine propose that HIV is co-opting a normal form of cell behavior—attaching itself to an email you were sending anyway.

In an article published in this week’s Nature, CRI postdoctoral fellow Kaushik Choudhuri, DPhil, and colleagues present evidence that HIV uses the same process that certain immune cells, called T cells, use to communicate with other immune cells.

T cells facilitate an immune response against pathogens—things like viruses or bacteria—and also against cancer. Receptors located on the surface of a T cell are like the cell’s “eyes,” allowing it to see and recognize signs of these dangerous invaders. When a T cell receptor recognizes and binds to a distinctive marker, or antigen, from a pathogen, the T cell becomes activated. Activated T cells kill infected cells directly and also signal other cells of the immune system to act, triggering an immune response.

T cells only stay active for a brief period of time, at which point they shut down their receptors. (This shutting down is necessary to prevent autoimmunity.) The accepted process by which T cells shut down their signaling is by internalizing the T cell receptors, smuggling them back inside the cell. But new research suggests that something different is going on.

What Choudhuri and colleagues have found is that immune cells also release T cell receptors (TCR) from the cell surface into the space outside the cell. Blobs of cytoplasm and membrane studded with TCRs pinch off from the cell and drift away, much like HIV particles do. They suggest that this budding serves two purposes: 1) it helps shut down an immune response; and 2) it packages up TCRs for delivery to neighboring immune cells awaiting news of invaders.

“Our discovery that TCR is shed in extracellular microvesicles suggests a radically different fate and function for TCR,” says Choudhuri, who works in the lab of Dr. Michael Dustin at NYU School of Medicine. “For instance we think that these microvesicles may convey intercellular messages to partner cells.”

Choudhuri says he and his colleagues were not thinking about HIV when they began their work. Rather, they were more interested in understanding the basic structure and function of the immunological synapse—the region of communication between two adjacent immune cells. It was only when they discovered that the TCR vesicle shedding process relies on the same protein machinery used in HIV budding that they suspected a link. They strengthened their case for a common mechanism by showing that HIV infection antagonizes, or competes with, the making of TCR vesicles.

It is a cruel irony that HIV infection appears to spread by co-opting the process by which immune cells communicate with each other. After all, the immune system is designed to protect us from invading pathogens. Communication between immune cells is necessary to keep us safe. HIV devilishly uses that same communication system to spread its deadly message from cell to cell.

This process may also suggest why HIV is so difficult to fully eradicate. Researchers have known for a long time that HIV infects CD4+ “helper” T cells, the depletion of which eviscerates the immune system and leaves the patient vulnerable to opportunistic infections. Other immune cells such as macrophages and dendritic cells also become infected but are not killed by the virus. These cells can become “reservoirs” of virus hiding out in the body.

“Despite a lot of progress in treating and controlling HIV infection, it is clear that the virus can persist in reservoirs in the body at low levels even with highly active retroviral therapy,” says Choudhuri. “We think that our results suggest a way for infected T cells to pass on the virus to these reservoirs—dendritic cells and macrophages, or even other T cells—especially when the infected T cells are interacting with these cells in response to an unrelated infection.”

Choudhuri’s research is relevant to more than HIV/AIDS. In addition to protecting us from infectious diseases, the immune system also wages a constant battle against cancer. By providing us with basic insights into how the immune system operates, Choudhuri’s work provides cancer immunologists with more tools with which to design better treatments. For example, his team is working on ways to make synthetic forms of these microvesicles that might serve to boost the immune system into fighting tumor cells.

Another reason this research is significant is that Choudhuri and his colleagues employed a powerful new approach to viewing cells at the ultramicroscopic level, one that marries cutting-edge light and electron microscopy techniques. “We anticipate that these techniques will unveil entirely new vistas of the cell biology of T cell activation,” Choudhuri says.

CRI has a long history of funding such basic immunological research, including research on HIV. In fact, CRI became an early funder of AIDS research in the 1980s when immunodeficient individuals began to develop Kaposi’s sarcoma, a rare type of skin cancer caused by a virus. CRI’s scientific leadership recognized that important insights could be gained by understanding the immunodeficiency–cancer link, and allocated $350,000 to AIDS research in 1983. Then medical director Lloyd J. Old, MD, said at the time, “AIDS is a major concern and a major mystery—a compelling problem that merits a special CRI program.” Among those researchers funded was Bijan Safai, MD, an expert on Kaposi’s sarcoma at Memorial Sloan-Kettering Cancer Center, who was one of the earliest investigators of the AIDS epidemic in New York City, and who was also part of the team of American researchers who pinpointed HIV as the cause of AIDS.

Since that time, CRI has awarded nearly $6 million in funding to more than 50 postdoctoral researchers working on HIV. Work from these researchers has provided us with an ever-more sophisticated understanding of how HIV acts to disrupt the immune system, paving the way for improved treatments not only for HIV, but also for cancer, allergies, and other immune-related diseases.