Impaired T Cell Function Can Lead to Loss of Ability to Suppress HIV

There is a small group of PLWH who are known as controllers and they can suppress HIV naturally with the help of their body’s cytotoxic T (CD8+ ) cells. When immune responses are working, cytotoxic T cells recognize antigens, which are found on the surface of infected cells, and the T cells then kill the infected cells and destroy the virus.

However, a small new study shows that when the cytotoxic T cells lose the ability to proliferate and kill HIV-infected cells, these PLWH no longer can suppress the virus naturally, and need antiretrovirals (ART) to control it. 

The study was published in Immunity.

“Loss of proliferation [cytotoxic T cells] was the most consistent predictor of aborted control in our study,” Principal investigator David Collins, PhD, fellow, Ragon Institute of MGH, MIT and Harvard, said. “In these cases, HIV-specific T cells gradually lost their ability to proliferate and become cytolytic, sometimes years before control was lost.”

Collins and the investigators compared samples from HIV controllers at Ragon and the University of California at San Francisco over several years. This small study included 17 subjects with aborted control and 17 with durable control, whose immune systems continued to suppress HIV over years of observation.

The team first looked at antigens and compared what type were presented by infected cells. When the team compared the two groups, they found that both sets of T cells responded to the same types of unlikely-to-mutate antigens.

The investigators looked more closely at the HIV-specific T cells in both groups, focusing on how well the T cells could perform their various functions. Cytotoxic T cells have 2 important functions when they encounter a cell presenting an HIV antigen. The first is their ability to kill infected cells by systematically rupturing them. The second function is their proliferative function: creating more HIV-specific T cells that can then hunt down and kill other infected cells.

In progressors—PLWH who cannot control the virus naturally and who require medication to suppress it—T cells quickly become desensitized to the HIV antigens and stop responding to them, a state known as T cell exhaustion. Researchers thought perhaps a similar process was happening to T cells when control was lost, but they found no such evidence. With the loss of control came a clear dysfunction of the T cells—the inability to kill cells infected by HIV—but it was a different type of dysfunction than was observed in most infections.

In the group of people who lost control of HIV, there was a measurable decrease in the proliferative and cytolytic ability of the T cells seen in samples taken before the loss of control, sometimes even years before. In addition, this dysfunction was only seen in response to HIV; the T cells were able to respond properly to other viral antigens.

The team next compared the genes expressed by the T cells in the 2 groups and found another important difference, one linked to their earlier observations. The T cells in the loss of control group had increased expression of KLF2, a gene that, when expressed at high levels, impairs the ability of T cells to proliferate.

“This study shows that loss of control is notably different from the inability to control the virus found in the canonical immune response to HIV,” says Ragon Director Bruce Walker, MD, and the paper’s senior author. “It further underlines the importance of a functional, effective T cell response to HIV in natural immune control of the virus. And with each secret HIV reveals comes an opportunity for us to use that knowledge to our advantage.”

This discovery may work towards treatments and vaccines that could train progressors’ immune systems. Further investigation is needed to understand why T cells become dysfunctional in some people and not in others.