Sometimes the most powerful weapons in maintaining health are the ones you cannot see with naked eyes. In immunology, T cells often wield the greatest power in fighting infection, allowing the body to recover from foreign invaders.

The severity of HIV is often measured in the number of a patient’s T cells, white blood cells with a crucial role in how the body’s immune system functions. HIV has proven proficient in killing T cells, rendering those with low T-cell counts susceptible to developing AIDS. Although existing therapies may help patients with HIV maintain a T-cell load that optimizes their immune function as much as possible, the treatment regimen for infected people is rigorous and adherence is difficult.

A key to fighting the virus once it has infected cells is therefore to understand what triggers, or activates, T cells in the first place so that they will amass their defenses to fight infection and call upon other cells that are needed to mount an effective immune response.

Building upon her years of success in HIV research, Terri Finkel, MD, PhD, chief of the Division of Rheumatology and Joseph Lee Hollander Endowed Chair in Pediatric Rheumatology, continues her pursuit by investigating T-cell activation and other biological functions that are key to understanding and battling HIV. She is currently investigating what starts the chain of events leading to T-cell activation, working closely with Zhengyu Ma, MD, PhD, a new research assistant professor at the CHOP Research Institute.

A T cell is activated after one of its receptors binds to a peptide complex on another cell — in the case of HIV infection, on an infected cell. The T-cell receptor and the peptide-loaded major histocompatibility complex, or pMHC, form a lock-and-key mechanism. However, Dr. Finkel and her colleagues have found that it isn’t the “locking” of the infected cell’s pMHC that triggers T-cell activation to fight infection and engage other cells needed in an immune response. Rather, T cells appear to be activated when these cells pull apart.

Dr. Finkel has turned her attention to a phenomenon between the cells called “rupture force,” created by the T cell essentially pulling back from the surface of a cell as it bounces along looking for the appropriate receptor. But the elusive nature of HIV and its ability to mutate in infected cells has compromised the critical rupture force needed for T-cell activation.

In HIV, the correct lock-and-key mechanism occurs between the T cell and peptide complex, but the virus is clever enough to change its peptide antigen, its lock. The T cell no longer recognizes the antigen as the one needed to achieve rupture force and fight an infection. T cells try to mount a force to deal with the new antigen but then HIV changes again.

Dr. Finkel is therefore exploring what specific part of the T-cell receptor is critical so it may one day be added back in through a gene therapy approach. Her colleague, Dr. Ma, is the first to use a process called atomic force microscopy to apply rupture force to T-cell receptors to eventually develop better T cells and receptors.

“What we are using to test this are receptors that have been put into T cells and have been shown to eliminate virus, at least in the test tube,” says Dr. Finkel. “Interestingly, they eliminate all strains of HIV. We are working with a company to design a super T-cell receptor that can recognize and kill cells that express a whole range of viruses. So even if the virus tries to escape, that lock-and-key mechanism is strong enough that the virus can’t get away.”

Dr. Finkel is looking to expand her HIV research program to use atomic force microscopy to further learn how T cells and other immune cells function, how infections evade the immune system, and how that system responds to foreign invaders.

She and her colleagues are also continuing their investigation of HIV latency, and have identified a new function for a viral protein, called Vif, which may be involved in HIV’s emergence from latency and allows the virus levels to soar within the body.

Future research may lead to the development of new drugs that target Vif and its cellular partners, or may bring infected cells out of latency so they can be treated with antiretroviral drugs.