Cytotoxic T cell impairment precedes losing control of natural HIV resistance

Sept. 10, 2021

Though most people with HIV need daily medication to suppress the virus and the development of AIDS, there is a small subset of people, known as controllers, that have immune systems that can suppress the virus without medication. While most controllers can suppress the virus indefinitely, some eventually lose control over the virus and require medication to achieve viral suppression.

According to a news release from Massachusetts General Hospital, researchers at the Ragon Institute of MGH, MIT and Harvard reported in Immunity that a type of immune cell, called a cytotoxic T cell, loses the ability to proliferate and kill HIV-infected cells.

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

When the immune response is successful, cytotoxic T cells recognize small pieces of HIV, called antigens, which are found on the surface of infected cells. The T cells then kill the infected cells, destroying the virus inside. If mutations in HIV were changing the antigens, the T cells may no longer be able to recognize them. Therefore, the most likely difference, the team thought, may be in the antigens themselves.

Previously, research showed that in controllers, cytotoxic T cells often recognize HIV antigens that are unlikely to mutate. When the team compared two groups, 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.

Next, they sequenced HIV from before and after 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 was not the answer, and there was no evidence of superinfection, the term for contracting a second, separate HIV infection. The difference, therefore, was likely in the immune response itself, instead of being driven by the virus.

Focusing on how well the T cells could perform their various functions, Cytotoxic T cells have two important functions when they encounter a cell presenting an HIV antigen. The first is their ability to kill infected cells by systematically rupturing them (called cytolysis). 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 — 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 known as T cell exhaustion. 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 researchers had thought that T cell dysfunction would come after or during loss of control, but here, the evidence shows that T cell dysfunction actually precedes it.

The team next compared the genes expressed by the T cells in the two 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.

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