HIV-Specific T Cells Lose Ability to Proliferate Over Time

In a paper recently published in Immunity, researchers at the Ragon Institute of MGH, MIT, and Harvard reported that in some cases, natural suppression of HIV is lost after cytotoxic T cells lose the ability to proliferate and kill infected cells.

First, the team compared what type of antigens were presented by infected cells. When the team examined the two groups—controllers and progressors—they found that both sets of T cells responded to the same types of unlikely-to-mutate antigens, meaning they were starting from similar immune responses. The researchers then next sequenced HIV from before and after the loss of control, looking for mutations that could cause changes in the antigens the T cells recognized. Even though HIV constantly mutates, within their cohort of 17 patients, they found only one mutation that allowed the antigen to escape T cell recognition. Mutational escape wasn’t the answer, either. There was also no evidence of superinfection, the term for contracting a second, separate HIV infection, another theory that had been suggested in case studies. The difference, therefore, was likely in the immune response itself, instead of being driven by the virus.

In progressors—people with HIV 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 is known as T cell exhaustion. 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 researchers had thought that T cell dysfunction would come after or during the loss of control, but here, the evidence shows that T cell dysfunction actually precedes it.

“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 senior author Ragon Director Bruce Walker. “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.”