Immune Activation, Proinflammatory Cytokines, and Conventional Risks for Cardiovascular Disease in HIV Patients: A Case-Control Study in Bahia, Brazil.

Carlos Brites,Ricardo Sohbie Diaz,Eduardo M Netto,Thalis Ferreira,Kimberly Page,Clara Brites-Alves,Celia Pedroso,Estela Luz

doi:10.3389/fimmu.2018.01469

Abstract

Cardiovascular events (CVE) are an increasing cause of morbi-mortality for HIV patients. The antiretroviral therapy (ART), persistent immune activation, and life style are factors that can increase CVE for such patients. We performed a case-control study to evaluate the role of coinfections and immune markers associated with CVE. We included patients under ART, with undetectable plasma viral load ≥12 months. Patients presenting any condition of risk for CVE were considered cases, and those without CVE risk conditions were controls. History of viral infections (Epstein-Barr virus, hepatitis C virus, hepatitis B virus, and cytomegalovirus), exposure to antiretroviral drugs, time since HIV diagnosis/under ART, and life style (demographics, weight, smoking, alcohol, and illicit drug use) were assessed. CD4/CD8 nadir and current counts, nadir and current CD4/CD8 ratio, immune activation markers (CD4CD38HLADR, CD8CD38HLADR), and serum levels of eight cytokines [IL-2, IL-4, IL-6, IL-10, tumoral necrosis factor-alpha (TNF-α), interferon gamma, macrophage inflammatory proteins 1 alpha, and interferon-inducing protein (IP-10)] were measured. Two-thirds of patients were males. Cases (N = 106) were older (52.8 vs 49.5 years, p = 0.002), had higher levels of creatinine (0.97 vs 0.87 mg/dL, p = 0.002) and IL-6 (0.67 vs 0.52 pg/mL, p = 0.04) than controls (N = 114). There was no difference between groups regarding frequency of CD4CD39HLADR+ or CD8CD38HLADR+ cells. We found a significant correlation (all patients) between increased frequency of CD4CD38HLADR+ cells and levels of IP-10 (r = 0.171, p = 0.02) and TNF-α (r = 0.187, p = 0.01). Levels of IL-6 (r = 0.235, p = 0.02), TNF-α (r = 0.267, p = 0.01), and IP-10 (r = 0.205, p = 0.04) were correlated with CD4CD38HLADR+ cells, in controls. Higher frequency of CD4CD38HLADR+ cells was also correlated with levels of IP-10 (r = 0.271, p = 0.04) in patients presenting with arterial hypertension. Frequency of CD4CD38HLADR+ cells was negatively correlated with levels of IL-2 (r = -0.639, p = 0.01) and IL-6 (r = -0.0561, p = 0.03) in patients with hypercholesterolemia. No association was detected between viral infections or smoking/alcohol use and immune activation markers. Our results indicate IL-6 levels are associated with increased CV risk. Activated CD4+ T cells were associated with increased levels of proinflammatory cytokines.

Highlights

The life expectancy of people living with HIV (PLHIV) has substantially increased over the last decades [1,2,3]
Higher frequency of CD4CD38HLADR+ cells was correlated with levels of inducing protein (IP)-10 (r = 0.271, p = 0.04) in patients presenting with arterial hypertension
When we looked at all patients, frequency of CD4CD38HLDR+ cells was significantly correlated with levels of IP-10 (r = 0.171, p = 0.02) and TNF-α (r = 0.187, p = 0.01), but not with IL-6 levels

Summary

Introduction

The life expectancy of people living with HIV (PLHIV) has substantially increased over the last decades [1,2,3]. A recent mathematical model (ATHENA Cohort) estimates that 73% of PLHIV will be older than 50 years by 2030 [5]. This trend has led to an increasing proportion of patients affected by non-communicable diseases (NCDs), in countries where antiretroviral treatment is available [5,6,7,8]. Increases in NCD causes of death include cancer (not related to HIV), diabetes, nephropathy, liver disturbances, and especially cardiovascular disease (CVD), comparable to seronegative individuals at similar age. The antiretroviral therapy (ART), persistent immune activation, and life style are factors that can increase CVE for such patients.

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Conclusion