Self-reactive T cells may explain why some patients can’t reach undetectable HIV levels

Despite the capability of antiretroviral drugs to suppress HIV to undetectable levels, some people living with the human immunodeficiency virus can’t reach the goal of viral imperceptibility even with daily doses of the potent medications.

It is a conundrum that has mystified virologists for years, but new research by a team of investigators at Johns Hopkins University in Baltimore, Maryland, has produced evidence that may explain why successful treatment eludes some patients living with HIV.

Based on a study of eight people whose antiretroviral treatment did not drive down HIV to an undetectable level, the Hopkins researchers found that constant HIV in the blood is not the result of patients missing medication doses or the virus becoming drug resistant. It persists, they discovered, because of a population of insidious immune components known as “self-reactive CD4⁺ T cells.”

Viral RNA in blood complicates therapy

These HIV-infected CD4⁺ T cells can release viral RNA that persists in the bloodstream, a phenomenon called nonsuppressible viremia. Simply put, nonsuppressible viremia refers to an ongoing presence of low levels of HIV in the blood.

“Antiretroviral therapy halts human immunodeficiency virus replication, reducing plasma virus concentrations to below the limit of detection, but it is not curative because of a reservoir of latently infected CD4⁺ T cells,” writes lead author of the study, Dr. Fengting Wu, in Science Translational Medicine.

“Even with 100% adherence to antiretroviral therapy, a large fraction of people living with HIV have residual viremia,” adds Wu, a molecular biologist.

“Nonsuppressible viremia remains a cause of distress for people living with HIV and their care providers,” Wu continued, noting in the study that “clinical options for managing nonsuppressible viremia are currently limited.”

She and the other Hopkins researchers also underscored that even though the viremia may be low, it cannot be controlled by simply upping the dosage of antiretroviral medication. So, despite doctors’ best efforts, viral RNA continues to persist in the blood. And more puzzling still, it may take years, even decades, for the viremia to emerge.

Nonsuppressible virus can emerge years later

The eight patients with nonsuppressible viremia were referred to the study by their physicians. All eight had been on long-term antiretroviral treatment for a median of 23 years before developing persistent viremia.

For the patient with the least amount of time on the therapy, it took nine years before nonsuppressible viremia occurred. Another spent 31 problem-free years on the treatment before viremia loomed as an inescapable fact of life. Yet, during the study period, some research participants who had lab-confirmed evidence of nonsuppressible viremia, had no signs of it at all.

“Several possibilities could explain the lack of detectable virus production from infected CD4⁺ T cells in some study participants,” writes Wu. “These include a low frequency of infected self-reactive cells, the antigen of interest not being present in the lysate, or the antigen being present at very low concentrations.”

Complicating matters further, CD4⁺ T cells make clones of themselves in HIV infection, a process known as clonal expansion. A small fraction of CD4⁺ T cells infected with HIV survive and divide, creating clones of infected cells that form the viral reservoir, the source of the nonsuppressible viremia.

Viral RNA in blood driven by CD4⁺ clones

The Hopkins team delved into the nature of the HIV viral reservoir by studying the contents of patients’ self-reactive CD4⁺ T cells. If the contents of the cells were revealed, they reasoned, a better understanding of what goes awry could be explained.

A preparation was made, which broke open the cells to release their contents. The team identified proteins, their fragments and pulped material, which can act as antigens.

Scientists additionally found in the lab that proviruses in CD4⁺ T cells are reactive to autologous antigens, thus contributing to nonsuppressible viremia. A provirus is the genetic material of a virus, such as HIV, that has been integrated into a host cell’s DNA. This integrated viral DNA becomes a permanent part of the host genome and can remain dormant before being “activated” to produce new viruses.

Indeed, the team discovered that T cells from the patients started producing HIV RNA when exposed to pulped material from the patient’s own cells. This RNA was identical to viral RNA that scientists isolated from the patients’ blood, suggesting that self-reacting T cells might be a major source of viral material in patients with nonsuppressible viremia. That finding led scientists to conclude the nonsuppressible viremia is driven by CD4⁺ T cell clones.

“These findings prompt future research efforts to better characterize the reactivity of infected clones responding to chronic antigens,” Wu and colleagues write, adding that such knowledge could inform individualized therapies that could benefit people living with HIV.

© 2025 Science X Network