January 29, 2013
Several years ago scientists discovered a link between T-cell dysfunction and the expression of a receptor named PD-1 on the T-cell surface. The initial discovery related to T cells in mice that had become functionally compromised due to battling a chronic viral infection (LCMV); it turned out that these exhausted T cells expressed very high levels of PD-1. Receptors like PD-1 can essentially be thought of as antennae on the outside of the cell that can interact with, and respond to, specific signaling molecules in the cell's environment. Depending on the signal, the receptor may sink back inside the cell to convey a message to the command center in the nucleus. This message in turn affects the behavior of the T cell and may lead to greater or lesser expression of the receptor. The PD-1 receptor can interact with at least two molecules (described as ligands): PD-L1 and PD-L2. Because high levels of PD-1 expression were associated with reduced T-cell function, researchers studied the effects of administering an antibody that targets PD-1 and thereby blocks its ability to interact with its ligands. The results of this experiment drew a lot of attention, because the strategy successfully rejuvenated the exhausted T cells and improved their ability to control LCMV replication. Similar laboratory findings were subsequently reported with T cells targeting cancers, leading to the development of anti-PD-1 antibodies as cancer therapies (an approach that has begun to show some success in human trials). PD-1 has also since been found to be highly expressed on exhausted HIV-specific T cells in humans, and a small study in macaques reported that PD-1 blockade reduced SIV viral load.
In addition to blocking PD-1, investigators are looking at the effects of an alternative strategy of targeting the ligand PD-L1. Brent Palmer and colleagues recently reported the first in vivo results obtained with this approach using the humanized mouse model of HIV infection. Encouragingly, the researchers found that blocking PD-L1 led to significant reductions in HIV viral load and preservation of CD4 T-cells counts without apparent adverse effects. Bristol Myers-Squibb supplied the anti-PD-L1 antibody for the study; the company is manufacturing it under the name BMS-936559 primarily for clinical trials in people with cancers.
The AIDS Clinical Trials Group (ACTG) currently has two research protocols in development that plan to investigate an anti-PD1 antibody (MK-3475, made by Merck) and the BMS-936559 anti-PD-L1 antibody in people with HIV infection. The studies will look at both T-cell function and effects on the latent HIV reservoir (due to evidence that latently infected CD4 T cells express high levels of PD-1). Safety will be the primary concern for these trials because PD-1 is also thought to be important in reducing the function of T cells that might otherwise be harmful (e.g., T cells capable of reacting with self antigens and causing autoimmunity).
Richard Jefferys is the coordinator of the Michael Palm HIV Basic Science, Vaccines & Prevention Project Weblog at the Treatment Action Group (TAG). The original blog post may be viewed here.