Curing HIV will almost certainly require harnessing the ability of the immune system to kill infected cells, or at least control their ability to produce the virus. One important tool in the immune arsenal is CD8+ T cells, sometimes also called killer T cells. Scientists have long suspected they play an important role in bringing virus levels under control soon after infection. amfAR grantees Drs. Ann Chahroudi, Guido Silvestri, Mirko Paiardini, and others at Emory University, along with colleagues from Harvard Medical School, the University of Pennsylvania, and the Frederick National Laboratory for Cancer Research, set about understanding whether the ability of CD8+ T cells to control HIV comes via a direct effect (e.g., killing HIV-infected cells or reducing the amount of virus they can produce) or an indirect effect (e.g., preventing virus from spreading to new target cells). In the September issue of the Journal of Virology, they describe some surprising findings.
As in humans, in most monkeys infected with SIV, the simian version of HIV, viral replication eventually reaches a plateau and stabilizes, with some individuals reaching a higher viral load (VL) than others. To understand how CD8+ T cells contribute to setting the viral load plateau, or set point, all of the animals in this study—those with high or low VLs—were treated with an antibody to deplete CD8+ T cells. As expected, the removal of the CD8+ T cells resulted in an increase in the amount of virus throughout the body, and the fold change in the low-VL animals was greater than in the high-VL group, confirming that the presence of CD8+ T cells had been keeping VLs low.
But how were the CD8+ T cells exerting these effects? The researchers identified a genetic switch, called T-bet, in CD8+ T cells that predicted how much virus was present after those cells were depleted. T-bet is known to be important in controlling a range of activities of immune cells, including their survival, development, and function as mature cells. Even more intriguing, they found that not all subsets of infected cells were affected equally by CD8+ T cell depletion. In the absence of CD8+ T cells to control the virus, it might be expected that there would be an increase in viral DNA as VL increases and new cells become infected. That was the case in monkeys with high VLs. Surprisingly, however, monkeys with low VLs had a decrease in one subset of cells known to harbor latent virus, called central memory T cells (TCM). The drop in TCM was observed in both blood and in tissues. The authors hypothesized this may have been due either to the differentiation of those cells into effector memory T cells or to the killing of TCM as a consequence of viral production that was previously controlled by CD8+ T cells.
The latter possibility is especially interesting in the context of research aiming to cure HIV by using an approach known as "shock and kill," in which infected cells are manipulated to produce more virus and then killed as a result. The role that CD8+ T cells may play in promoting the death of virus-producing cells remains unclear and worthy of further study.
Dr. Johnston is amfAR's vice president and director of research.