HIV "Elite Controllers" Are Characterized by a High Frequency of Memory CD8+CD73+ T Cells Involved in the Antigen-Specific CD8+ T-cell Response

Abstract

Human immunodeficiency virus type 1 (HIV-1) infection is characterized by chronic immune activation and suppressed T-lymphocyte functions. Here we report that CD73, both a coactivator molecule of T cells and an immunosuppressive ecto-enzyme through adenosine production, is only weakly expressed by CD8+ T cells of HIV-infected patients and only partially restored after successful antiviral treatment. CD73 expression on CD8+ T cells correlates inversely with cell activation both ex vivo and in vitro. However, CD8+ T cells from HIV controllers (HICs), which spontaneously control HIV replication, express CD73 strongly, despite residual immune activation. Finally, we demonstrate that CD73 is involved in the HIV-specific CD8+ T-cell expansion. Thus, we show that CD73 is central to the functionality of HIV-specific CD8+ T cells and that the preservation of HIV-specific CD73+ CD8+ T cells is a characteristic of HICs. These observations reveal a novel mechanism involved in the control of viral replication.

Normal T-cell activation in elite controllers with preserved CD4+ T-cell counts

“…A prior publication showed an inverse correlation between CD73 expression and CD8 T cell activation [13]. We too observed a negative correlation for the combined EC group which was most likely driven by the EC hi group (figure 4B).…”

“…Additionally, in this group, maintenance of CD28 expression, a co-stimulatory molecule which is commonly reduced during chronic HIV infection was retained. A recent study found that CD73, a coactivator of T cells [13] was elevated in all EC. However our data shows that this is only observed for the EC hi group and therefore cumulatively indicates that the EC hi group manifests a phenotype of functionally responsive T cells that is similar to healthy seronegative adults.…”

“…Notably, polyfunctional T cells, capable of cytokine secretion, proliferation, and cytotoxicity are maintained in these controllers [4–9]. Additional important aspects of their T cell function have been reported, including low levels of T-cell activation [10], up regulation of survival factors such as bcl-2 [11], up regulation of cyclin dependent kinase inhibitors such as p21 [12] and higher frequency of expression of costimulatory molecule CD73 [13]. Furthermore, cells from EC are less susceptible to infection and effectively suppress in-vitro HIV replication [8, 14].…”

Down-regulation of CD73 on B cells of patients with viremic HIV correlates with B cell activation and disease progression

“…Moreover, a distinct role for CD39 has been shown in the suppression of T effector cell functions [18]. Parallel to the expansion of CD39 + regulatory T cells, general down-regulation of CD73 on all T cell subsets was observed in HIV infection, which correlated with immune activation and functional defects of these cells [21,23,26,27].…”

T cell receptors for the HIV KK10 epitope from patients with differential immunologic control are functionally indistinguishable

“…CTLs from HCs mediate more efficient HIV inhibition in vitro (10)(11)(12), polyfunctional secretion of cytokines such as IL-2 and IFN-γ (1,10,11), greater antigeninduced proliferation (10,13), less T cell activation (4), and evasion of regulatory T cell suppression (14). CTLs from HCs may also be phenotypically more inclined to protect from HIV infection for long durations (9,15) and sustain effector functions without T cell exhaustion (16). Several HLA-I alleles, including B*2705 and B*5701, are enriched in HCs (17,18), underscoring the role of CTLs in suppressing HIV infection.…”