Immune Exhaustion Occurs Concomitantly With Immune Activation and Decrease in Regulatory T Cells in Viremic Chronically HIV-1–Infected Patients

Abstract

Background Chronic HIV-1 infection is associated with excessive immune activation as well as immune exhaustion. We investigated the relationship of these two phenotypes and frequency of regulatory T cells (Tregs) in controlled and uncontrolled chronic HIV-1 infection. Methods Immune exhaustion marker PD-1, its ligand PD-L1, CD4+CD25brightFoxP3+ Tregs, HLA-DR and CD38 coexpression as activation markers were investigated in peripheral blood lymphocytes of 44 HIV-1 infected patients and 11 HIV-1 uninfected controls by multi-color flow cytometry. Results Activated and PD-1 expressing T cells were increased and Tregs were decreased in HIV-1 infected patients as compared to controls, and alterations were greatest in viremic patients. The proportion of activated CD8+ T cells exceeded activated CD4+ T cells. Tregs had an inverse correlation with activated T cells and PD-1 expressing T cells. PD-L1 was highly expressed on monocytes and to a lesser extent on T lymphocytes of patients. These abnormalities partially reversed with virologic control following potent antiretroviral therapy (ART). Conclusions Immune exhaustion is a component of aberrant immune activation in chronic HIV-1 infection and is associated with loss of Tregs and ongoing virus replication. These defects are corrected partially with effective virologic control by potent ART.

4-1BB Signaling Synergizes with Programmed Death Ligand 1 Blockade To Augment CD8 T Cell Responses during Chronic Viral Infection

“…The connection between excessive immune activation and exhaustion has been widely documented (32–34). Caution should be taken with therapies based on costimulatory regimens to ensure optimal cell longevity and function.…”

Reevaluation of immune activation in the era of cART and an aging HIV-infected population

“…The finding of reduced CD38 expression with age was not unexpected since it is expressed on double-positive thymocytes and thymus function declines steadily through at least age 60 (32). However, CD38 expression on T cells (especially CD8) has also been extensively studied and implicated as a correlate of HIV disease progression (33)(34)(35) and further, coexpression with HLA-DR on the surface of T cells is a widely accepted measure of IA (9,10,36). Therefore, we expected that HIV + would exhibit differential expression patterns of CD38 on T cells compared with HC.…”

Association between discordant immunological response to highly active anti-retroviral therapy, regulatory T cell percentage, immune cell activation and very low-level viraemia in HIV-infected patients

“…Recently, some authors postulated that they might play a role in iIR [14,27]. However, this subject is also currently the matter of intense debates [14,[28][29][30][31][32][33][34][35]. Moreover, during HIV infection, the circulating proportion of effector Tregs and terminal effector Tregs, as described recently by Sakaguchi et al [36], and interaction between Tregs and VLLV are not clearly established.…”