Virologically Suppressed HIV Patients Show Activation of NK Cells and Persistent Innate Immune Activation

Abstract

FcRγ is an ITAM-containing adaptor required for CD16 signaling and function in NK cells. We have previously shown that NK cells from HIV patients receiving combination antiretroviral therapy (cART) have decreased FcRγ expression, but the factors causing this are unknown. We conducted a cross-sectional study of cART-naive viremic patients (ART−), virologically suppressed patients receiving cART (ART+), and HIV-uninfected controls. CD8+ T cells were activated, as assessed by CD38+HLA-DR+ expression, in ART− patients (p < 0.0001), which was significantly reduced in ART+ patients (p = 0.0005). In contrast, CD38+HLA-DR+ NK cells were elevated in ART− patients (p = 0.0001) but did not decrease in ART+ patients (p = 0.88). NK cells from both ART− and ART+ patients showed high levels of spontaneous degranulation in ex vivo whole blood assays as well as decreased CD16 expression (p = 0.0001 and p = 0.0025, respectively), FcRγ mRNA (p < 0.0001 for both groups), FcRγ protein expression (p = 0.0016 and p < 0.0001, respectively), and CD16-dependent Syk phosphorylation (p = 0.0001 and p = 0.003, respectively). HIV-infected subjects showed alterations in NK activation, degranulation, CD16 expression and signaling, and elevated plasma markers of inflammation and macrophage activation, that is, neopterin and sCD14, which remained elevated in ART+ patients. Alterations in NK cell measures did not correlate with viral load or CD4 counts. These data show that in HIV patients who achieve viral suppression following cART, NK cell activation persists. This suggests that NK cells respond to factors different from those driving T cell activation, but which are associated with inflammation in HIV patients.

Anti-HIV Antibody–Dependent Activation of NK Cells Impairs NKp46 Expression

“…Chronic HIV infection that induces ongoing activation of NK cells due to ADCC would be expected to elicit in vivo phenotypic and functional changes in NK cells similar to those observed after in vitro activation (i.e., reduced CD16 expression, hyporesponsiveness, and reduced NKp46 expression) (26)(27)(28)(29)39). Indeed, HIV infection results in a set of dysfunctional NK cell changes similar to that observed after CD16-mediated activation in vitro (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22). Thus, we speculate that continued activation of NK cells as a result of ADCC during untreated chronic viral infections could explain the reduced functionality of NK cells observed during HIV infection.…”

“…Similarly, several studies (11,14,17,22) reported decreased NK cell-mediated ADCC by HIV-infected patients. Lastly, HIV infection is associated with a decreased expression of the activating natural cytotoxicity receptors (e.g., NKp30, NKp44, NKp46) and CD16, as well as an increased expression of inhibitory killer cell Iglike receptors (KIRs) (13,(15)(16)(17)(18)(19)(20). Alterations in the expression of these receptors likely have a significant negative impact upon the ability to respond to infections and malignant conditions.…”

“…Furthermore, the recently completed RV144 vaccine trial, which was modestly protective in the absence of strong broadly neutralizing Ab or cytotoxic T cell responses, induced Abs capable of mediating ADCC that may have been related to the observed protection (8)(9)(10). Despite the immense interest in using ADCC for therapeutic purposes, it should be noted that NK cells exhibit extensive phenotypic alterations and dysfunction during HIV infection (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22). However, it is unclear whether chronic activation of NK cells via ADCC could contribute to this disease-related dysfunction.…”

“…Upon ex vivo analyses, NK cells from HIV-infected individuals exhibit altered phenotype, function, and subset distribution (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22). Infection with HIV was observed to coincide with the appearance of a hypofunctional CD16 + CD56 2 subset and a decrease in the highly functional CD16 + CD56 dim subset (12,21).…”

Cellular Pharmacology and Potency of HIV-1 Nucleoside Analogs in Primary Human Macrophages

“…Multiple reports define ongoing chronic inflammation and immune activation in HIV-infected patients, even in those with well-controlled viremia (22)(23)(24). Elevated levels of IL-6, tumor necrosis factor alpha (TNF-␣), and IL-1␣/␤ largely hallmark these events.…”