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Any evolutionary reason for the interaction between these lectins and LAG3 is unclear but likely dependent on the heavy glycosylation of LAG3. LAG3 differs from other ICs because it lacks noticeable inhibitory motifs. However, this same study showed that mutating a lysine residue in the cytoplasmic domain abolished LAG3 function, implying an intracellular mechanism rather than receptor competition. A potential explanation for this apparent paradox is that LAG3 inhibits intracellular signaling proteins dependent on CD4 or CD8, such as lymphocyte-specific protein tyrosine kinase Lck.

Furthermore, LAG3 maintains its role on non—T-cells, as discussed below. Therefore, LAG3 may also function in TCR-independent stimulations such as through cytokine or pattern recognition receptors. Therefore, more research into the LAG3 mechanism and situational roles is critical. We propose several possible mechanisms for this curiosity Fig 1. Although LAG3-mediated regulation protects T-cells from activation-induced cell death following intense stimulation, LAG3 offers no protection from apoptosis following physiologically relevant stimulation [ 7 , 14 , 55 ].

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. Likewise, Treg LAG3 expression is higher than for conventional T-cells [ 59 , 60 ]; its role on Tregs remains controversial. In contrast, studies using similar models show LAG3 inhibiting Treg function and impairing Treg development [ 29 , 62 , 63 ]. One consistent finding throughout these studies is that LAG3 inhibits proliferation of Tregs.

Yet, pDC-mediated immune activation may also contribute to immunopathology and immune exhaustion [ 65 ]. These immunosuppressive and trans -cellular LAG3 effects may explain why LAG3 knockout mice have increased numbers of cell types that naturally lack LAG3—including granulocytes and macrophages [ 67 ]—suggesting that LAG3 inhibits expansion of other innate immune cells by encouraging a suppressive environment.

An early report showed LAG3-knockout or -blockade enhancing murine-NK killing of tumor cell lines [ 69 ]; however, a contrasting study was unable to confirm this in human NKs [ 70 ]. Although their antiviral function is not clear, MAITs respond to bacterial metabolites and are likely important in defence against bacterial coinfections during HIV [ 75 ].

Innate T-cells are more abundant in the gut and liver than peripheral blood. These are sites of intense inflammation during HIV infection, suggesting LAG3 expression in these areas may be even greater than in the blood. Due to complex immune environments and severe immune-mediated liver damage often caused by these phasic infections, further study is needed to determine whether LAG3 is harmful or beneficial.

Overall, LAG3 is understudied on innate cells. Immune exhaustion is a main facet of immune dysfunction and is associated with poor HIV disease outcomes. Indeed, LAG3 is associated with high viral load [ 11 , 19 , 83 ], faster disease progression [ 19 ], and rapid return of viraemia following treatment interruption [ 83 ]. These studies do not resolve cause from effect, because LAG3 may represent immune activation rather than contribute to disease progression, but they demonstrate that LAG3 is associated with unfavourable disease measurements and could be a main contributor to immune exhaustion in HIV.

Reversing immune exhaustion may restore immunity against coinfections and enhance HIV-specific immunity, making it a candidate for use in a functional cure. Elite controllers demonstrate that such control is possible. LAG3-blockade could be one component of this strategy by reversing latency and simultaneously enhancing HIV-specific immunity Fig 1.

Although studies have not investigated whether LAG3 helps maintain HIV latency, studies have shown that PD1-blockade enhances latency reversal and exposes HIV in latently infected cells to the adaptive immune system for potential elimination [ 87 — 91 ]. Reversing immune exhaustion could effectively restore this immunity. Indeed, only a short duration of LAG3-blockade enhances the formation of memory T-cells during viral infections [ 14 , 93 ].

As an approved first-line treatment for advanced melanoma, research into PD1-blockade is more developed than for LAG3-blockade. Furthermore, PD1-blockade improves frequency and response of HIV-specific CTL, and reduces viral load and mortality in simian immunodeficiency virus-infected macaques, indicating exhaustion in HIV is reversible [ 90 , 96 ].

Promising PD1-blockade studies in humanized mice [ 97 ] and ex vivo [ 94 ] have resulted in early clinical trial attempts to improve anti-HIV immunity. However, retinal toxicity in a parallel macaque model study led to this human trial being stopped. This adverse event slowed IC-blockade research for HIV and warrants caution, although a recent similar study witnessed no side effects [ 90 ]. It is unclear whether IC-blockade for HIV is any less safe than for cancer; however, HIV necessitates a different risk—benefit calculus for IC-blockade compared to cancer, with similar risk but lower benefit considering the alternative of lifelong ART.

Therefore, a main concern surrounding IC-blockade for HIV is that it may increase inflammation and immune activation, thereby accelerating disease. Although a valid concern, the preliminary successes of PD1-blockade support the argument that reversing immune exhaustion will result in favorable outcomes. Regardless, LAG3 and other IC-blockades should be investigated in HIV models with and without viral suppression to understand their roles during disease.

Providing ART is a priority; therefore checkpoint inhibition should be pursued for individuals with ART-suppressed virus. For untreated individuals, checkpoint blockade may increase cellular production of and susceptibility to HIV by enhancing immune activation. Therefore, during viral suppression, IC-blockades would likely be most effective when combined with triggers or other immunotherapies Fig 2. Immunotherapies like IC-blockade have advantages, including almost no risk of HIV resistance and potentially improved broad immunity, particularly against coinfections.

These advantages and the potential for a functional cure justify cautious optimism and further research of LAG3 expression, mechanism, and function. After administering this vaccine, checkpoint blockade could feasibly enhance LRAs 2 activity as previously demonstrated for PD1 [ 91 ]. Author summary Antiviral drugs have transformed HIV infection from a death sentence to a manageable disease. Introduction Antiretroviral therapy ART inhibits human immunodeficiency virus HIV replication, but a reservoir of latently infected cells means that ART must be taken indefinitely and thus does not constitute a cure.

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