Roles, function and relevance of LAG3 in HIV infection

Abstract

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.

Fig 1. LAG3 on T-cells during HIV infection.

HIV induces inflammation and immune activation, which leads to exhausted lymphocytes and increased expression of LAG3 and HLA-DR, an HLA class II molecule. LAG3 may inhibit CTL activation by binding to (1) the alternative LAG3 ligands LSECtin or Gal3, (2) HLA class II molecules that traffic to the immune synapse on the target cell or (3) HLA class II molecules that traffic to the immune synapse on the same cell, or by (4) cotrafficking with CD8 to the immune synapse, which occurs during CD8 crosslinking [109]. Productive HIV infection increases production of Gal3, which can inhibit CTL activation and killing. Productive infection can be induced from latent infection through activation of certain transcription factors, including NFAT, which is inhibited by LAG3 during T-cell activation. CD, cluster of differentiation; CTL, cytotoxic T lymphocytes; Gal3, Galectin-3; HLA, human leukocyte antigen; LAG3, lymphocyte activation gene-3; LSECtin, liver and lymph node sinusoidal endothelial cell C-type lectin; NFAT, nuclear factor of activated T-cells; TCR, T-cell receptor.

Fig 2. Potential role for checkpoint blockade in combination immunotherapy for a functional cure.

A therapeutic vaccine (1) would enhance HIV-specific CTL number and function. Because many HIV-specific CTLs are exhausted during HIV, IC blockade could enhance the activating effect of the vaccine and the function of the CTL after activation. After administering this vaccine, checkpoint blockade could feasibly enhance LRAs (2) activity as previously demonstrated for PD1 [91]. During LRA treatment, broadly neutralizing antibodies (3) could bind to HIV polypeptide expressed on the infected cell’s surface and activate antibody dependent cell cytotoxicity activity by NK cells, which may also be enhanced by checkpoint blockade [110]. CD4, cluster of differentiation 4; CTL, cytotoxic T lymphocyte; HLA, human leukocyte antigen; IC, immune checkpoint; LRA, latency reversing agent; NK, natural killer; PD1, programmed cell death-1; TCR, T-cell receptor.