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Plasma levels of cytokines and chemokines and the risk of mortality in HIV-infected individuals: a case-control analysis nested in a large clinical trial
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24 April 2015
French, Martyn A.a,b; Cozzi-Lepri, Alessandroc; Arduino, Roberto C.d; Johnson, Margarete; Achhra, Amit C.f; Landay, Alang; for the INSIGHT SMART Study Group aSchool of Pathology and Laboratory Medicine, University of Western AustraliabDepartment of Clinical Immunology, Royal Perth Hospital and PathWest, Laboratory Medicine, Perth, AustraliacResearch Department of Infection and Population Health, University College London, London, United KingdomdHouston AIDS Research Team, Division of Infectious Diseases, The University of Texas Health Science Center at Houston, Houston, USAeHIV Clinic and Department of Respiratory Medicine, Royal Free Hospital, London, United KingdomfKirby Institute, University of New South Wales, Sydney, AustraliagDepartment of Immunology and Microbiology, Rush University Medical Center, Chicago, USA.
All-cause mortality and serious non-AIDS events (SNAEs) in individuals with HIV-1 infection receiving antiretroviral therapy are associated with increased production of interleukin-6 which appears to be driven by monocyte/macrophage activation. Plasma levels of other cytokines or chemokines associated with immune activation might also be biomarkers of an increased risk of mortality and/or SNAEs.
Methods: Baseline plasma samples from 142 participants enrolled into the Strategies for Management of Antiretroviral Therapy study, who subsequently died, and 284 matched controls, were assayed for levels of 15 cytokines and chemokines. Cytokine and chemokine levels were analysed individually and when grouped according to function (innate/proinflammatory response, cell trafficking and cell activation/proliferation) for their association with the risk of subsequent death.
Results: Higher plasma levels of proinflammatory cytokines (interleukin-6 and tumour necrosis factor-α) were associated with an increased risk of all-cause mortality but in analyses adjusted for potential confounders, only the association with interleukin-6 persisted. Increased plasma levels of the chemokine CXCL8 were also associated with all-cause mortality independently of hepatitis C virus status but not when analyses were adjusted for all confounders. In contrast, higher plasma levels of cytokines mediating cell activation/proliferation were not associated with a higher mortality risk and exhibited a weak protective effect when analysed as a group.
Conclusion: Whereas plasma levels of interleukin-6 are the most informative biomarker of cytokine dysregulation associated with all-cause mortality in individuals with HIV-1 infection, assessment of plasma levels of CXCL8 might provide information about causes of mortality and possibly SNAEs.
HIV-1 infection results in immune activation through several mechanisms. This contributes to CD4+ T-cell depletion and to activation of inflammatory and coagulation pathways which contributes to the pathogenesis of serious non-AIDS events, including atherosclerotic vascular disease, osteoporosis, osteonecrosis and chronic kidney disease [1,2]. Although CD8+ T-cell activation is an established marker of immune activation in HIV patients [3], plasma markers of monocyte/macrophage activation, including interleukin-6 levels, are better predictors of serious non-AIDS events [4,5]. Monocyte activation is associated with atherosclerotic vascular disease, neurocognitive decline and increased mortality [6-9], in part by activation of coagulation pathways [10,11].
Patients with HIV-1 infection receiving antiretroviral therapy (ART) who cease therapy exhibit plasma cytokine and chemokine changes that provide a signature of monocyte/macrophage activation, particularly increased production of interleukin-6 and tumour necrosis factor-alpha (TNF-α) [12]. It is well established that high plasma interleukin-6 levels are associated with morbidity and mortality in HIV patients [13-15] but unclear if increased production of other cytokines or chemokines is associated with an increased risk of death. We have, therefore, examined baseline plasma levels of cytokines and chemokines in Strategies for Management of Antiretroviral Therapy (SMART) study participants who died during study follow-up and compared them with baseline levels in matched controls.
Our analysis of baseline plasma cytokine and chemokine levels in individuals with HIV-1 infection enrolled into the SMART study has demonstrated that none of the cytokines and chemokines examined was associated with an increased risk of all-cause mortality to the same degree as interleukin-6 [13,14]. Indeed, higher plasma levels of cytokines that induce cell activation and proliferation showed a trend towards a protective effect on all-cause mortality. However, we have provided preliminary evidence that increased production of CXCL8 might contribute to an increased mortality risk. This evidence included an analysis of analytes by functional grouping which demonstrated that the association with mortality was at least as strong for the cell-trafficking group (CXCL8 and CXCL10) as it was for innate/proinflammatory group (interleukin-6, TNF-α and interleukin-1-ß), although this may reflect the dilution of the strong association with interleukin-6 by the weaker associations with TNF-α and interleukin-1-ß. In addition, when the effect of other cytokines and chemokines on the association of interleukin-6 with mortality was examined, CXCL8 demonstrated the greatest effect. Our findings, therefore, raise the possibility that increased production of CXCL8 contributes to an increased mortality risk in individuals with HIV-1 infection.
Chemokines, including CXCL8, CCL2 [also known as monocyte chemotactic protein-1 (MCP-1)] and CXCL1 [also known as growth related oncogene-α (GRO-α)], play important roles in the migration and adhesion of monocytes to atherosclerotic plaques in vascular endothelium [18,19]. Furthermore, production of CXCL8 and other chemokines is decreased by statin therapy [20-23]. We therefore suggest that chemokines associated with the pathogenesis of atherosclerosis, such as CXCL8, are candidate biomarkers of atherosclerotic vascular disease in patients with HIV-1 infection. This should be addressed in future studies.
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