The immune system is the gatekeeper of our well-being. It must constantly monitor itself to ensure that it is not under- or overreacting to any given stimulus. Underactivation of the immune system is one hypothesis for the development of cancer, because the immune system fails to recognize when a normal process become pathogenic. Overactivation, on the other hand, causes an attack against our own tissue leading to autoimmune diseases.
Immune checkpoints (ICs), present on the surface of cells, are powerful molecular brakes used by our immune system specifically to prevent overactivation. These inhibitory signals are typically balanced by activating immune signals, and together they orchestrate an appropriate and tempered immune response. When the scales tip toward the inhibitory signaling of ICs, however, it can be difficult to energize the immune cell to fight pathogens. The scientific term for this reticence is ‘exhaustion,’ and during some chronic viral infections our immune system becomes too exhausted to fight, in part because of the expression of ICs.
Researchers at this year’s International AIDS Society Conference in Vancouver in July presented studies aiming to revive the ‘exhausted’ immune system of chronically infected HIV individuals by using so-called immune checkpoint blockers (ICBs). Work led by amfAR grantee Dr. Mirko Paiardini of Emory University in Atlanta showed a higher level of expression of CTLA4, one of several ICs currently being studied, in cells harboring latent HIV. The presence of CTLA4 makes these cells more difficult to activate by “shock and kill” (also sometimes referred to as “kick and kill”) approaches, thus making it more difficult to eradicate the latent HIV reservoir from these cells.
Exciting work presented by Glen Michael Chew of the Ndhlovu lab at the University of Hawaii, showed the reactivation of cells from chronically infected individuals by blocking TIGIT, a more recently described IC. Furthermore, by combining the TIGIT blocker with a drug that blocks a separate IC, PD-L1, a synergist improvement in the function of HIV specific killer cells was found.
Dr. Sharon Lewin of the University of Melbourne recently received a $2 million amfAR grant to pursue ICB-related studies. Her group will study two ICBs, alone and in combination, for their ability to activate latently infected cells and reduce the latent reservoir in HIV-positive patients.
There is good reason to be hopeful that these ICB-directed therapies, as part of a “shock and kill” approach, will succeed in reenergizing the immune system and enhancing its ability to eliminate HIV. ICB therapy in cancer has already revolutionized the field and has all but cured certain forms of the disease.
Dr. Flores is amfAR’s associate director of research.