In HIV infection populations of immune system cells are devastated, but researchers have found one immune cell type that survives the onslaught.

These surviving cells prevent inflammation, but they do so by suppressing the immune system. This new finding raises the question of whether their survival during HIV infection helps the body or the attacking virus.

The cells, called T regulators, may be useful because they normally prevent a hyperactive immune system which leads to its exhaustion.

But in the case of HIV infection their role of suppression could be disastrous, if this effect means the immune system causes its own demise by shutting itself down in a time of crisis. Knowing the difference could eventually help develop new HIV treatments, and this will be a central question guiding future research.

The reason why the Jekyll and Hyde nature of T regulators (T-regs) are being found now, after thirty years of HIV research, is because researchers are looking in a new place, one that has been harder to investigate.

Ever since the identification of HIV cases in the 1980s, HIV’s effect on the immune system has been the primary means by which the severity of the Human Immunodeficiency Virus is judged. Yet, despite the immune system’s central role in HIV, scientists had not studied the region of the body where most immune cells are located: the gut.

According to HIV researcher Douglas Kwon, eighty percent of our immune cells are located in the gut—the esophagus, stomach, and small and large intestines. The gut is where most HIV replication takes place and thus where most immune cells start to disappear. This led Kwon and other researchers to study the effect of HIV on this section of the body more closely, even though studying the gut can be complicated and costly.

Each gut sample yields only a small fraction of information that a similar type of sample obtained from the blood would—tens of thousands of cells instead of millions. Gut cells are obtained by taking biopsies, removing small bits of tissue material from live patients, each about the size of a grain of rice. Altogether, the biopsy costs between five to ten thousand dollars.

Using similar techniques, researcher Barbara Shacklett of the University of California, Davis, reports in the Journal of Virology the role of T-regs, a subcategory of T cells, in the gut. She found that the absolute number of T-regs remains roughly the same throughout the progression of HIV infection, indicating that the immune system, above all else, creates T-regs to replace lost immune cells.

This finding is counterintuitive because the general population of immune system cells decreases dramatically following an HIV infection. Thus, the ratio of T-regs compared to other T cells increases substantially over time. Furthermore, the primary function of T-regs is to act as an immune system suppressant. Why the immune system would choose to suppress its own response in a time of crisis is puzzling.

On the other hand, the role of T-reg as an anti-inflammatory prevents the immune system from becoming hyperactive. Chronic inflammation, says Kwon, can lead to advanced aging effects (cardiovascular disease, hypertension, and osteoporosis) in young people with HIV even with expensive retroviral drug treatment.

“The role of T-reg in HIV infection is rather controversial. These cells may play a beneficial role for the host in limiting inflammation and shutting down an immune response that is no longer needed. However, in the case of HIV infection, they may act inappropriately to curtail beneficial immune responses,” writes Shacklett.

The potentially conflicting roles of T-regs with HIV has led several researchers, including Shacklett, to devote most of their time and energy into figuring out which function is more important in mitigating the effects of HIV in the body.

Maryln Addo is also currently studying T-regs, but in the blood, and her results confirm the conundrum Shacklett recently found in the gut. Addo says that the mystery of why T-regs above all other cell types continue to be created by the immune system despite an ongoing, overwhelming HIV onslaught is a messy and controversial subject, and not only for the T-reg roles.

T-reg research remains controversial, she says, because identifying a T-reg from an activated general T cell is difficult. Although T cells, a type of white blood cell, have been studied for decades, the role of T-regs had been largely overlooked both in gut and in the bloodstream because there was no marker to differentiate them from other types of T cells populating the immune system.

In email correspondence from an immunology conference in Europe, Shacklett writes, “Our lab has traditionally focused on T cells in the gut (as opposed to the blood); this is because in the mid-1990s it was shown that HIV infection causes a rapid and profound depletion of the CD4-expressing T cells in the gut—even more extensive than what is seen in the blood.” CD4 is an immune cell marker that serves as a proxy for the extent of immune depletion caused by HIV and can also help identify T-regs.

Besides CD4, there are other markers that in combination can now be used to uniquely identify T-regs from the general T cell population. Addo says that these marker combinations, some of which have only been recently described, enables researchers to reliably count T-regs.

However, other researchers remain skeptical that the studies to date have successfully applied such a technique. One such researcher in Kwon’s lab points out that FOXP3 and CD25 are the classical markers to monitor the T-reg population, yet some of Shacklett’s T-reg count is based only on the CD25 count.

This is because the CD25 is a non-descript surface marker on the immune cell while the FOXP3 marker is located inside. Therefore, CD25 is easier to detect than FOXP3. Additionally, because the FOXP3 count is internal, it can kill the cell in the process. This means you can no longer perform functional experiments on the cell because it is dead.

However, despite the FOXP3 drawbacks, say critics, the problem with a CD25-only approach is that CD25 is also a marker for T cell activation, so a CD25 by itself cannot differentiate a T-reg from an activated T cell. Since you do not know if you are looking at a T-reg or an activated T-cell, according to these critics, the marker methodology Shacklett chose in some of the data means that she could not properly count the number of T-regs.

The controversy over the T-reg role and their perceived hardiness in the face of HIV annihilation (known through what other skeptical researchers say is still an uncertain science) means that it will take more research to determine to what extent T-regs are helpful or harmful in the context of HIV.

The question of why these cells are still standing long after HIV has ravaged other immune cells could explain the runway effect which causes HIV to progress to full blown AIDS, and more generally help us understand how T-regs contribute to—and inhibit—the way our immune system works.