Evidence for Innate Immune System Activation in HIV Type 1–Infected Elite Controllers

Krishnan, Sonya; Wilson, Eleanor; Sheikh, Virginia; Rupert, Adam; Mendoza, Daniel; Yang, Jun; Lempicki, Richard A.; Migueles, Stephen A.; Sereti, Irini

doi:10.1093/infdis/jit581

Cited by 121 publications

(107 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This was the first report of the monocyte subset distribution in primary HIV-1 infection, and it expanded previous observations that had focused on chronic HIV-1-infected patients, HARRT patients, and elite controllers. 16,17,30 In contrast to the report by Han et al, 16 we found that CD14 dim CD16 1 and CD14 high CD16 2 monocytes were negatively correlated with CD4 counts in PHI but not CHI. This difference might be due to our limited case numbers in the CHI group.…”

Section: Monocyte Subset Frequencies Are Altered During Hiv-1 Infectioncontrasting

confidence: 94%

Higher levels of circulating monocyte–platelet aggregates are correlated with viremia and increased sCD163 levels in HIV-1 infection

Liang

Duan

et al. 2014

Cell Mol Immunol

View full text Add to dashboard Cite

Increased levels of monocyte-platelet aggregates (MPAs) are reported to be highly correlated with cardiovascular events. In this study, the MPA levels in different monocyte subsets and the associations between MPA levels, HIV-1 viremia and monocyte activation were evaluated during HIV-1 infection. The results showed that the percentages of MPAs in all three monocyte subsets were higher in HIV-1-infected subjects than in healthy controls, and were associated with the plasma viral load in the non-classical and intermediate monocyte subsets. The plasma levels of sCD14 and sCD163 were upregulated in HIV-1 infection and were positively associated with viral loads and negatively associated with CD4 counts. P-selectin glycoprotein ligand-1 (PSGL-1) was shown to be expressed at significantly lower levels on all three monocyte subsets and was negatively correlated with the sCD163 level. The MPA level was correlated with the levels of plasma sCD163 but negatively correlated with CD163 and PSGL-1 on all three monocyte subsets. An elevated immune activation status was correlated with increased MPA formation, underlying the potential interaction between monocyte activation and MPA formation. This interaction may be related to a higher thromboembolic risk in patients infected with HIV-1.

show abstract

Section: Monocyte Subset Frequencies Are Altered During Hiv-1 Infectioncontrasting

confidence: 94%

Higher levels of circulating monocyte–platelet aggregates are correlated with viremia and increased sCD163 levels in HIV-1 infection

Liang

Duan

et al. 2014

Cell Mol Immunol

View full text Add to dashboard Cite

show abstract

“…"Elite controllers" (HIV + individuals who control HIV viremia without ART) also display innate immune activation (9), suggesting it may be independent of HIV viremia and cART. Instead, the causes may include residual HIV replication in tissues (10,11), reactivation of latent viruses such as CMV (12,13), and/or the presence of circulating bacterial products due to loss of gut integrity (4).…”

mentioning

confidence: 99%

An NK Cell Population Lacking FcRγ Is Expanded in Chronically Infected HIV Patients

Zhou

Amran

Kramski

et al. 2015

The Journal of Immunology

View full text Add to dashboard Cite

We previously demonstrated that NK cells from HIV-infected individuals have elevated expression of activation markers, spontaneously degranulate ex vivo, and decrease expression of a signal-transducing protein for NK-activating receptors, FcRγ. Importantly, these changes were maintained in virologically suppressed (VS) individuals receiving combination antiretroviral therapy (cART). In this study, we show that loss of FcRγ is caused by the expansion of a novel subset of FcRγ−CD56dim NK cells with an altered activation receptor repertoire and biological properties. In a cross-sectional study, FcRγ− NK cells as a proportion of total CD56dim NK cells increased in cART-naive viremic HIV-infected individuals (median [interquartile range] = 25.9 [12.6–56.1] compared with 3.80 [1.15–11.5] for HIV− controls, p < 0.0001) and in VS HIV-infected individuals (22.7 [13.1–56.2] compared with 3.80 [1.15–11.5], p = 0.0004), with no difference between cART-naive and VS patients (p = 0.93). FcRγ− NK cells expressed no NKp30 or NKp46. They showed greater Ab-dependent cellular cytotoxicity activity against rituximab-opsonized Raji cells and in a whole-blood assay measuring NK responses to overlapping HIV peptides, despite having reduced CD16 expression compared with conventional NK cells. Their prevalence correlated with CMV Ab titers in HIV− subjects but not in HIV+ individuals, and with the inflammatory marker CXCL10 in both groups. The expansion of a subset of NK cells that lacks NKp30 and NKp46 to ∼90% of CD56dim NK cells in some VS HIV+ individuals may influence NK-mediated immunosurveillance in patients receiving cART.

show abstract

“…In addition, skewed differentiation of monocytes into proinflammatory CD16 ϩ monocytes and tumor necrosis factor alpha (TNF-␣)-producing M-DC8 ϩ CD14 ϩ CD16 ϩϩ monocytes during chronic HIV-1 infection have been observed in the presence of HIV-1 viremia compared to that observed in HIV-1 seronegative subjects (7,9,17). 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.…”

Section: Abstract Cyld Hiv-1 Inflammatory Responses Mir-126-5p Momentioning

confidence: 99%

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

Huang

Zhu

Qiu

et al. 2017

J Virol

View full text Add to dashboard Cite

Persistent immune activation during chronic human immunodeficiency virus type 1 (HIV-1) infection facilitates immune dysfunction and thereby fuels disease progression. The translocation of bacterial derivatives into blood and the hyperinflammatory responsiveness of monocytes have been considered important causative factors for persistent immune activation. Whether microRNAs (miRNAs) are involved in regulating monocyte-mediated inflammatory responses during chronic HIV-1 infection remains elusive. In this study, we show that miR-126-5p functions as a positive regulator of monocyte-mediated inflammatory responses. Significantly increased miRNA miR-126-5p and decreased cylindromatosis (CYLD) were observed in primary monocytes from chronic HIV-1 patients. Inhibition of miR-126-5p in monocytes from chronic HIV-1 patients attenuated the responsiveness of these cells to lipopolysaccharide (LPS) stimulation. Gain-of-function assays confirmed that miR-126-5p could downregulate CYLD, which in turn caused an upregulation of phosphorylation of JNK protein (pJNK) and enhanced inflammatory responses of monocytes to LPS stimulation. Overall, miR-126-5p upregulates the responsiveness of monocytes to LPS stimulation in chronic HIV-1 infection, and the suppression of miR-126-5p and the promotion of CYLD expression in primary monocytes may represent a practical immune intervention strategy to contain persistent inflammation in chronic HIV-1 infection.IMPORTANCE Monocyte-mediated hyperinflammatory responses during chronic HIV-1 infection are important causative factors driving AIDS progression; however, the underlying mechanism has not been fully addressed. We demonstrated that miR-126-5p, one of the most upregulated miRNAs during chronic HIV-1 infection, could enhance the inflammatory responses of monocytes to LPS by suppressing the inhibitory protein CYLD and thereby unleashing the expression of pJNK in the LPS/ Toll-like receptor 4/mitogen-activated protein kinase pathway. This observation reveals a new mechanism for HIV-1 pathogenesis, which could be targeted by immune intervention.

show abstract

Evidence for Innate Immune System Activation in HIV Type 1–Infected Elite Controllers

Abstract: Elite controllers maintain control of plasma HIV viremia and have evidence of an activated innate immune response.

Cited by 121 publications

References 49 publications

Higher levels of circulating monocyte–platelet aggregates are correlated with viremia and increased sCD163 levels in HIV-1 infection

Higher levels of circulating monocyte–platelet aggregates are correlated with viremia and increased sCD163 levels in HIV-1 infection

An NK Cell Population Lacking FcRγ Is Expanded in Chronically Infected HIV Patients

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

Contact Info

Product

Resources

About