Expression of Chemokine and Inhibitory Receptors on Natural Killer Cells: Effect of Immune Activation and HIV Viremia

Abstract

We examined the cell-surface expression of chemokine and natural killer (NK) cell inhibitory receptors (iNKRs) on NK cells from individuals with human immunodeficiency virus (HIV) infection, chronic hepatitis C infection, and Wegener's granulomatosis (WG), an inflammatory, granulomatous vasculitis. The expression of CCR5 on NK cells was up-regulated in individuals with HIV viremia and in individuals with active WG, indicating that expression of this receptor is modulated by states of immune activation associated with viral infection and inflammatory or immune-mediated diseases. In contrast, iNKRs were shown to be up-regulated only on NK cells of individuals with HIV viremia, and they returned to a normal level when viremia was controlled with effective antiviral therapy. In individuals with HIV-1 viremia, there was a direct correlation between the level of expression of p58.1, p58.2, and CD94 receptors and plasma HIV viremia, suggesting that ongoing active HIV replication has an effect on the expression of such receptors on NK cells. These results suggest that immune activation leads to abnormal cell-surface expression of chemokine receptors on NK cells, whereas HIV-specific processes account for the up-regulation of iNKRs on NK cells; this may explain the NK cell-functional defects seen in HIV infection.

Selective Serotonin Reuptake Inhibitor and Substance P Antagonist Enhancement of Natural Killer Cell Innate Immunity in Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome

“…In addition to producing chemokines, NK cells also secrete cytokines, including interferon γ (INF-γ), tumor necrosis factor (TNF), and granulocyte/ macrophage colony-stimulating factor (GM-CSF), which may produce further inhibition of HIV replication (81,82). Natural killer cells may have a key regulatory role in controlling HIV infection, and there are adverse effects of HIV on NK cell function, including reduced lysis of HIV-infected cells, reduced production of CC chemokines, and reduced secretion of cytokines (5,(83)(84)(85). Thus, specific impairments in NK cell function may compromise the host's natural resistance against HIV.…”

Increased Natural Killer Cell Activity in Viremic HIV-1 Infection

“…It remains unclear as to the mechanism by which NK cell depletion occurs. Although a single study suggested that direct infection of activated NK cells (30) may play a part in the loss of NK cells, a separate report demonstrated increased CCR5 expression on the surface of NK cells potentially contributing to the sequestration of NK cells in infected tissues (31). In addition, general immune activation associated with HIV-1 infection may lead to increased apoptosis of NK cells, and thus, a depletion of this cell subset.…”

Characterization of CD56–/CD16+natural killer (NK) cells: A highly dysfunctional NK subset expanded in HIV-infected viremic individuals

“…We and others have reported that the expression and function of inhibiting and activating NK receptors are dysregulated in NK cells of HIV-infected viremic individuals (12)(13)(14)(15). To determine whether this abnormal expression of NK receptors was preferentially associated with a particular NK subset, we analyzed their expression on CD56 Ϫ and CD56 ϩ populations of freshly isolated NK cells by using flow cytometry.…”

“…More recently, numerous studies have characterized the effects of HIV viremia on NK cell phenotype and function. In this regard, it has been demonstrated that the expression and function of most major iNKRs are either maintained or significantly increased on the surface of NK cells in viremic patients (12,13), and a direct correlation has been reported between these findings and levels of HIV viremia (14). Moreover, the expression of natural cytotoxicity receptors (NCRs), NKp46, NKp30, and NKp44, is markedly decreased among viremic individuals, along with a concomitant decrease in NK cytolytic activity (13,15).…”