Roles, function and relevance of LAG3 in HIV infection

HIV causes several forms of immune dysfunction that need to be addressed in a functional cure for HIV. Immune exhaustion describes a dysfunctional phenotype caused by chronic cellular activation. Lymphocyte activation gene-3 (LAG3) is one of several negative coreceptors known as immune checkpoints that contribute to this exhaustion phenotype. Antibodies targeting immune checkpoints are now used clinically to restore immunity against cancer and hold promise in restoring immunity during HIV infection. Here, we summarize current knowledge surrounding LAG3 and discuss its relevance during HIV infection and the potential for LAG3-targeting antibodies in a functional HIV cure. Author summary Antiviral drugs have transformed HIV infection from a death sentence to a manageable disease. However, millions still lack access to these drugs, which require daily adherence. This allows the HIV epidemic to continue, killing a million people each year. The search for a cure has been long, but researchers now have a greater knowledge of HIV and human biology than ever before and are designing drugs and strategies that may be used in a cure. Checkpoint blockade is one strategy already used to treat cancer but may also eventually be used in an HIV functional cure, which would allow the body to control HIV without the help of antiviral drugs. Checkpoint blockade works by inhibiting molecules called immune checkpoints, which are the brakes of the immune system. Here we focus on an immune checkpoint called LAG3. LAG3 can be present on many different immune cells with differing frequency but is more abundant during HIV, in which having more LAG3 is associated with certain aspects of worse disease. Although it may have slightly different functions on different types of cells, overall, LAG3 reduces the cell's ability to respond to stimulus. Inhibiting LAG3 could reinvigorate immune cells to fight HIV and may even help fight coinfections such as hepatitis viruses. Inhibiting other immune checkpoints along with LAG3 may improve efficacy. If combined with other drugs and strategies to fight HIV, checkpoint blockade may allow the immune system to control HIV without the help of antiviral drugsa functional cure.