One of the immune activation profiles observed in HIV-1-infected adults with suppressed viremia is linked to metabolic syndrome: The ACTIVIH study

Abstract

Immune activation in HIV-1-infected individuals is reduced under antiretroviral therapies, but persists, resulting in various morbidities. To better characterize this phenomenon, using a panel of 68 soluble and cell surface markers, we measured the level of activation in circulating CD4+ and CD8+ T cells, B cells, monocytes, NK cells, polynuclear and endothelial cells as well as of inflammation and fibrinolysis in 120 virologic responders over 45 years of age. As compared with age- and sex-matched uninfected individuals, we observed a persistence of activation in all the cell subpopulations analyzed, together with marks of inflammation and fibrinolysis. Two independent hierarchical clustering analyses allowed us to identify five clusters of markers that varied concurrently, and five patient groups, each with the same activation profile. The five groups of patients could be characterized by a marker of CD4+ T cell, CD8+ T cell, NK cell, monocyte activation or of inflammation, respectively. One of these profiles was strongly associated with marks of metabolic syndrome, particularly with hyperinsulinemia (OR 12.17 [95% CI 1.79–82.86], p = 0.011). In conclusion, our study unveils biomarkers linked to metabolic syndrome that could be tested as predictive markers, and opens the way to new therapeutic approaches tailored to each patient group.

Insulin Resistance in HIV-Patients: Causes and Consequences

“…Chronic immune activation and insulin resistance can contribute to obesity, dyslipidemia, CVDs, and non-alcoholic fat liver disease (NAFLD) as well as neurocognitive disorders, metabolic disorders, bone abnormalities, and non-HIV associated cancers ( 12 , 97 , 98 , 99 ). While the evolution of these complications depends on genetic and environmental factors, each condition has the potential of aggravating another (Figure 2 ).…”

Identification of Immune Activation Profiles That May Predict Morbidity During Antiretroviral Therapy Treated HIV Infection

“…The Strategies for the Management of Antiretroviral Therapy (SMART) study demonstrated that plasma levels of interleukin-6 (IL-6), C-reactive protein, and D-dimer are independent predictors of mortality in HIV infection, including deaths related to cardiovascular disease (CVD) ( Kuller, LH, et al, 2008 , Emery, S, et al, 2008 ). The predictive value of markers of immune activation and inflammation has been confirmed in several studies ( Psomas, C, et al, 2016 , Hunt, PW, et al, 2014 , Kalayjian, RC, et al, 2010 ). Potential mechanisms have also been identified that may contribute to increased activation of both the innate and the adaptive immune systems in chronic HIV infection, including: copathogens, microbial translocation, pro-inflammatory lipids, low level viral replication, and the immune system's response to cytopenia ( Lederman et al, 2013 ).…”

“…In their manuscript in EBioMedicine , Psomas and colleagues used a combination of 68 markers of immune activation and inflammation and two independent hierarchical clustering analyses to identify 5 donor groups from among 120 HIV-infected virologic responders ( Psomas et al, 2016 ). These donor groups were characterized using combinations of activation markers among CD4 + T cells, CD8 + T cells (CD38, HLA-DR, CD279, CD57), B cells (serum levels of IgG, IgA, IgM) natural killer cells (HLA-DR, CD69), monocytes (soluble CD14 and sCD163), and markers of inflammation and coagulation.…”

“…The authors claim that they can identify these donor groups using a single flow cytometry panel that includes 8 markers; while this could widen the potential utility of the authors' identification strategy, it will still need to be validated in diverse clinical settings. Also, it is not clear to what degree these panels offer a significant advance in the ability of a clinician to predict morbidity or progression of comorbid disease states when compared to indices that are measured as part of routine care, or when compared to other individual biomarkers that have been linked previously to disease outcomes ( Kuller, LH, et al, 2008 , Emery, S, et al, 2008 , Psomas, C, et al, 2016 , Hunt, PW, et al, 2014 , Kalayjian, RC, et al, 2010 , Tenorio, AR, et al, 2014 ). The association between increased levels of TNFR-I and the prevalence of metabolic syndrome is not entirely surprising, as inflammation plays a key role in modulation of lipid levels, including decreased levels of high density lipoprotein (HDL), increased levels of low density lipoprotein (LDL), and decreased cholesterol efflux ( Tall and Yvan-Charvet, 2015 ).…”

Deregulated MicroRNA-21 Expression in Monocytes from HIV-Infected Patients Contributes to Elevated IP-10 Secretion in HIV Infection

“…Antiretroviral therapy (ART) extends the lifespan and the quality of life of HIV-infected patients while completely eliminating chronic immune activation and inflammation does not occur ( 3 , 4 ). Persistent inflammation contributes to immune senescence and exhaustion, factors linked to most non-AIDS-related complications of HIV, such as cardiovascular, neurocognitive, and metabolic syndromes ( 2 – 5 ). A comprehensive understanding of the molecular and cellular basis of the inflammatory status allows these remaining challenges of HIV treatment to be addressed.…”