Science Editor

Untreated HIV is almost invariably fatal - in fact, in the early days of the pandemic, the unique terror of HIV was that it was almost a surefire death sentence.

But even before treatments were available, a tiny group of long-term survivors or "elite controllers" defied the odds, living for years with HIV infection without progressing to AIDS.

In the May 6, 2010, advance online edition of Nature, scientists described one of the reasons for why elite controllers are able to keep HIV infection at bay in the absence of treatment. The discovery adds to the understanding of what makes for an effective immune response to the virus, and could aid in vaccine design.

The findings "by no means open up an unobstructed path to a vaccine," corresponding author Bruce Walker told BioWorld Today. But they do add to the understanding of what an effective vaccine might do - which, basic as it may seem, remains an only partially solved problem. "At this point in the epidemic, we are still trying to understand what a good immune response to HIV might look like," Walker said.

Elite controllers are a much-studied group of HIV patients, and scientists already knew that they are likely to have certain variants of HLA molecules - surface proteins on antigen-presenting cells that bind the proteins those cells show to B cells and T cells.

In their paper, Walker, corresponding author Arup Chakraborty and their colleagues suggested that the details of T-cell development in the thymus influence how well T cells will be able to control HIV, and possibly other fast-mutating viruses as well.

Mature killer T cells recognize viral peptides presented by HLA molecules on the surface of infected cells, and kill the cells that present them. Before they join the body's fighting forces, T cells go through a complex maturation process in the thymus. Chakraborty likened the thymus to T-cell school, albeit a draconian one: Cells that fail their exams are put to death.

The goal of T-cell school is to weed out T cells that bind peptides either not strongly enough, which would make them ineffective at fighting foreign invaders, or too strongly, which would make them likely candidates for causing autoimmune problems.

In the thymus, T cells bind to HLA molecules presenting a variety of host-derived peptide fragments, and only those binding with intermediate strength receive critical maturation signals. But how varied that variety is depends on a person's HLA variants. Through a combination of clinical and modeling studies, the team determined that HLA-B57 - one particular HLA variant that is often found in elite controllers - presents fewer different fragments than other HLA variants. In effect, Chakraborty said, HLA-B57 presents a "less stringent exam" to developing T cells. Consequently, more T cells that bind strongly to certain peptide fragments will successfully get through the thymus, because the T cells are less likely to encounter those peptides and be weeded out during their development.

One consequence of such strong binding is that elite controller T cells are more likely to still be able to recognize point mutants of the peptides they bind to - and that, in turn, makes them more able to control HIV as the virus mutates. "It is not the only factor" determining elite controller status," Chakraborty said. "But it is a newly identified contributing factor."

Of course, HLA status is not something that a vaccine can influence. But the differences in T-cell binding are not absolute. In normal individuals, Walker said, 1 in a million T cells with strong binding characteristics might slip through, whereas in elite controllers, the proportion is higher. "It's not that [strongly binding T cells] are not present" in nonelite controllers, Walker said. "It's just that they are less frequent." But it might be possible to design vaccine epitopes that encourage such binding - or it might be possible to somehow "fish out" the rare T cells and encourage them to expand.

Walker said that the major strength of the findings, for now, is that they provide a goal that vaccines can strive for. "We know what we want," he said, "and that helps us devise the strategies to get what we need."