Matrix Metalloprotease Inhibitors Restore Impaired NK Cell-Mediated Antibody-Dependent Cellular Cytotoxicity in Human Immunodeficiency Virus Type 1 Infection

Abstract

Increasing evidence suggests that NK cells not only are critical in the initial host defense against pathogens but also may contribute to continued protection from human immunodeficiency virus type 1 (HIV-1) disease progression. NK cell cytolysis can be induced directly through diverse receptor families or can be induced indirectly through Fc receptors by antibodies mediating antibody-dependent cellular cytotoxicity (ADCC). ADCC has been implicated in both protection from simian immunodeficiency virus infection and slower progression of HIV-1 disease. ADCC activity declines with advancing infection, and yet the underlying mechanism for this dysfunction has not been defined, nor has it been determined whether the activity can be reconstituted. Here we demonstrate that NK cell-mediated ADCC is severely compromised in chronic HIV infection. The potency of ADCC function was directly correlated with baseline Fc␥RIIIa receptor (CD16) expression on NK cells. CD16 expression was negatively influenced by elevated expression of a group of enzymes, the matrix metalloproteinases (MMPs), normally involved in tissue/receptor remodeling. Inhibition of MMPs resulted in increased CD16 expression and augmented ADCC activity in response to antibody-coated target cells. These data suggest that MMP inhibitors may improve NK cell-mediated ADCC, which may provide subjects with an opportunity to harness the cytolytic power of NK cells through naturally occurring nonneutralizing HIV-specific antibodies.

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

“…Loss of CD16 has been shown to be partially dependent on matrix metalloproteinase induction, which promotes shedding of the extracellular domain of the receptor (30). Our data showing a direct correlation of CD16 mRNA expression with CD16 surface expression indicate that an additional mechanism regulating CD16 surface expression at a transcriptional level is operating in chronic 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.…”

“…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).…”

“…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.…”