IFN-Stimulated Gene LY6E in Monocytes Regulates the CD14/TLR4 Pathway but Inadequately Restrains the Hyperactivation of Monocytes during Chronic HIV-1 Infection

Abstract

Owing to ongoing recognition of pathogen-associated molecular patterns, immune activation and upregulation of IFN-stimulated genes (ISGs) are sustained in the chronically infected host. Albeit most ISGs are important effectors for containing viral replication, some might exert compensatory immune suppression to limit pathological dysfunctions, although the mechanisms are not fully understood. In this study, we report that the ISG lymphocyte Ag 6 complex, locus E (LY6E) is a negative immune regulator of monocytes. LY6E in monocytes negatively modulated CD14 expression and subsequently dampened the responsiveness to LPS stimulation in vitro. In the setting of chronic HIV infection, the upregulation of LY6E was correlated with reduced CD14 level on monocytes; however, the immunosuppressive effect of LY6E was not adequate to remedy the hyperresponsiveness of activated monocytes. Taken together, the regulatory LY6E pathway in monocytes represents one of negative feedback mechanisms that counterbalance monocyte activation, which might be caused by LPS translocation through the compromised gastrointestinal tract during persistent HIV-1 infection and may serve as a potential target for immune intervention.

The Upregulation of LAG-3 on T Cells Defines a Subpopulation with Functional Exhaustion and Correlates with Disease Progression in HIV-Infected Subjects

“…Human subject protocols were followed as previously described (30). The lower detection limit for HIV-1 RNA is 50 copies/ml.…”

MicroRNA miR-126-5p Enhances the Inflammatory Responses of Monocytes to Lipopolysaccharide Stimulation by Suppressing Cylindromatosis in Chronic HIV-1 Infection

“…The basic characteristics of the studied subjects have been previously published (13,71). All of the HIV-1 patients were infected by blood transmissions during 1995 or 1996 and were enrolled in the study and have been followed up six times per year since 2009.…”

“…All of the HIV-1 patients were infected by blood transmissions during 1995 or 1996 and were enrolled in the study and have been followed up six times per year since 2009. For this study, 15 out of 37 ART-naive (ART Ϫ ) patients and 12 out of 19 ART-treated (ART ϩ ) patients were randomly selected based on the classification described in previous research (13,14,71). HIV-1-seronegative subjects were recruited from the Shanghai Public Health Clinical Center as healthy controls.…”

“…Monocyte activation and inflammation are commonly found in chronic human immunodeficiency virus type 1 (HIV-1) patients (6)(7)(8)(9)(10)(11). The translocation of bacterial derivatives from the compromised gastrointestinal (GI) tract into the blood observed in chronic HIV-infected subjects (1,5,12) and the hyperresponsiveness of monocytes to lipopolysaccharide (LPS) have been considered impor-tant causative factors for persistent immune activation (6,13). Preexposure of monocytes to Toll-like receptor 7/8 (TLR7/8) ligands derived from HIV-1 single-stranded RNA (ssRNA) (14,15) and upregulated TLR2 expression on monocytes (16) could enhance the inflammatory responsiveness of these cells.…”

“…Effective antiretroviral therapy (ART) successfully suppresses HIV-1 replication but fails to normalize monocyte activation/inflammation (3,(18)(19)(20)(21). Our previous report shows that interferon-stimulated gene lymphocyte antigen complex 6, locus E (LY6E), in monocytes regulates the CD14/TLR4 pathway but inadequately restrains the hyperactivation of monocytes during chronic HIV-1 infection (13), indicating the presence of additional mechanisms to promote the inflammatory responses of monocytes.…”