Immunological dysfunction in HIV‐1‐infected individuals caused by impairment of adenosine deaminase‐induced costimulation of T‐cell activation

Abstract

Summary The cell surface association between CD26 and adenosine deaminase (ADA) has a costimulatory function during T‐cell activation. Several studies have revealed correlations among CD4+ CD26+ T‐cell depletion, increased serum levels of ADA, and the evolution of human immunodeficiency virus (HIV) infection, implicating CD26 and ADA in HIV disease progression. In this context, we aimed to determine whether ADA costimulation could be altered during HIV infection. ADA costimulation was investigated in cells from HIV‐infected patients (n = 36) in terms of proliferation and cytokine secretion. An effect of ADA on T‐cell proliferation was found in HIV‐1‐infected patients and correlated positively with the CD4+ percentage and the nadir CD4 count and negatively with viral load, demonstrating that the response depends on the immunological status of the patient. The robust ADA‐induced increase in cytokine production [interferon (IFN)‐γ, interleukin (IL)‐6 and IL‐10] was markedly reduced in T cells from HIV‐1‐infected subjects. To eliminate some of the variables associated with immunological defects in HIV‐1‐infected patients, anti‐CD3 plus ADA assays with T cells from healthy volunteers were performed in the presence of recombinant glycoprotein 120 (gp120). It was found that gp120 was responsible for the impairment of the ADA–CD26 interaction and consequently of the ADA‐induced effect on both costimulation and cytokine production. The gp120‐mediated disruption of the CD26–ADA interaction is a novel mechanism that might explain, at least in part, the altered immunological features observed in HIV‐1‐infected patients and may have significant relevance in AIDS pathogenesis.

Adenosine deaminase potentiates the generation of effector, memory, and regulatory CD4+ T cells

“…Furthermore, it has been described that ADA binding to CD26 is inhibited by soluble rHIV-1 envelope glycoprotein gp120 and by HIV-1 infectious particles [49]. Importantly, whereas ADA-CD26-mediated costimulation of T cell activation is impaired in HIV-1-infected patients [24], we here show that ADA-mediated costimulation promotes potentiation in the generation of Teffs and memory T cells in a similar extent to that observed in cocultures from healthy individuals. Thereby, exogenous addition of ADA could increase effector response and generation of CD4 ϩ memory T cells against HIV.…”

“…This ADA-mediated costimulation not only potentiates T cell proliferation but also the secretion of Th1 (IFN-␥) and proinflammatory (IL-6 and TNF-␣) cytokines [8]. Importantly, we have recently described that this ADA-mediated costimulation is attenuated in CD4 ϩ T cells obtained from HIV-infected individuals, which contributes to the immunodeficiency [24]. However, when exogenous ADA is added on a coculture of HIV-pulsed DCs and autologous T cells, it is possible to generate a HIV-specific T cell response.…”

“…These results indicate that ADA enhanced the TCR-mediated generation of Teffs, but it had no effect by itself. The ADA-mediated, costimulatory effect on CD4 ϩ T cell proliferation is impaired in HIV-infected individuals [24]. Thereby, the question of whether the generation of Teffs is attenuated in cocultures obtained from HIV-infected patients, compared with healthy donors, was investigated.…”

Dendritic cell based vaccines for HIV infection

“…17,18 and that the HIV envelope glycoprotein gp120 markedly reduces this effect. 19 These results could help to explain, at least in part, the progressive impairment of the immune system in HIV-infected patients.…”

“…17 By acting as a bridge between A 2B adenosine receptors on dendritic cells (DCs) surface and CD26 on T-cells surface, ADA acts as a costimulatory molecule in cocultures of SEA-presenting DCs and autologous T cells, not only enhancing T-cell proliferation, Th-1/pro-inflammatory cytokine secretion, 17 and naïve T-CD4 + cell activation, memory, and FOXP3 + generation, 18 but also increasing DCs immunogenicity in both healthy and HIVinfected subjects. 63 Although HIV gp120 envelope protein disrupts ADA-CD26 interaction, 64 possibly contributing to the HIV-promoted immunodeficiency, 19 ADA is still able to enhance autologous T-cell proliferation against inactivated-HIV presentation by DC in individuals under cART (Fig. 3), 16 suggesting a beneficial role for ADA on improving HIV-specific T-cell responses in those individuals.…”