Revisiting Immune Exhaustion During HIV Infection

Abstract

Chronic immune activation is a hallmark of HIV infection, yet the underlying triggers of immune activation remain unclear. Persistent antigenic stimulation during HIV infection may also lead to immune exhaustion, a phenomenon in which effector T cells become dysfunctional and lose effector functions and proliferative capacity. Several markers of immune exhaustion, such as PD-1, LAG-3, Tim-3, and CTLA-4, which are also negative regulators of immune activation, are preferentially upregulated on T cells during HIV infection. It is not yet clear whether accumulation of T cells expressing activation inhibitory molecules is a consequence of general immune or chronic HIV-specific immune activation. Importantly, however, in vitro blockade of PD-1 and Tim-3 restores HIV-specific T-cell responses, indicating potential for immunotherapies. In this review we discuss the evolution of our understanding of immune exhaustion during HIV infection, highlighting novel markers and potential therapeutic targets.

The Upregulation of LAG-3 on T Cells Defines a Subpopulation with Functional Exhaustion and Correlates with Disease Progression in HIV-Infected Subjects

“…Blockage of the LAG-3 pathway by LAG-3-Fc fusion proteins significantly increased T cell responses, as quantified by IFN-g-based assays, suggesting that the LAG-3-mediated impairment of T cell functionalities was at least partially reversible and could be recovered by interrupting the LAG-3/MHC II pathway. In this regard, LAG-3, similarly to PD-1 (6,7,47), could be considered as a T cell functional regulatory receptor and, as shown in this study, is mainly expressed on effector T cells. The second consequence is enhancement of the threshold to initiate fresh T cell responses.…”

“…Under this circumstance, the immune system may fail to initiate a fresh T cell response against a less immunogenic mutated HIV epitope or may require a prolonged period of time to tackle an immunogenic mutant HIV epitope. Similarly, an HIV-infected individual is likely to have difficulty fighting off a subsequent coinfection (47).…”

Post-treatment control of HIV infection

“…We associate a high killing rate with a strong immune response. Effector cells are assumed to be produced at rate λ E and to be lost at rate μ. Effector cells proliferate in an infected cell densitydependent manner with maximum rate b E , where the proliferation term is b E (I /(K B + I))E. High viral loads (and therefore high infected cell densities) may induce some immune impairment, e.g., immune exhaustion (36,37). Allowing for the rate of this impairment to saturate, we model the loss of functional effector cells by the term d E (I /(K D + I))E, where K D is chosen larger than K B .…”

Antigen-Independent Induction of Tim-3 Expression on Human T Cells by the Common γ-Chain Cytokines IL-2, IL-7, IL-15, and IL-21 Is Associated with Proliferation and Is Dependent on the Phosphoinositide 3-Kinase Pathway

“…Mechanisms of immune evasion include viral escape via epitope mutations, as well as the induction, directly or indirectly, of negative immune regulatory proteins, such as programmed death 1 (PD-1), CTLA-4, and T cell Ig mucin domaincontaining molecule 3 (Tim-3), on the surface of Ag-specific T cells (1)(2)(3). Overexpression of these molecules on effector T cells dampens immunological control against infected cells, manifested by the failure of T cells to proliferate in response to Ag and by an inability to secrete effector cytokines, such as IFN-g and TNF-a, in some cases leading to apoptosis.…”