Immunology of Hypertension in People With HIV

I n the modern antiretroviral therapy (ART) era, people with HIV (PWH) are living longer and the leading causes of death in PWH are now cardiovascular disease (CVD), non-AIDS malignancies, and liver disease. The risk of CVD in PWH is 2.5-fold higher than in HIV-uninfected adults, and HIVassociated CVD contributes to 2.6 million disability-associated life-years annually. Hypertension is the leading risk factor for CVD in PWH. Globally, hypertension ranks as the strongest risk factor for CVD and causes >10 million deaths and 200 million disability-adjusted life-years per year. A recent meta-analysis indicates that the prevalence of hypertension in PWH on ART is 35% and increasing. Data suggest that PWH and concurrent hypertension may experience an even higher risk of CVD than similar hypertensive HIV-negative adults. Novel pathophysiologic mechanisms may drive hypertension in PWH. HIV-specific mechanisms for hypertension may include microbial translocation, renin-angiotensin-aldosterone system activation, lipodystrophy, dyslipidemia, adipokines, renal disease, sympathetic activation, endothelial dysfunction, arterial stiffness, immune reconstitution, and/or chronic inflammation. The individual contribution of these components to hypertension in PWH is currently unknown, and specific pathways remain understudied. In this issue of the Journal of the American Heart Association (JAHA), Masenga et al begin to fill this critical gap by reporting immune phenotyping results from 70 PWH with and without hypertension. All PWH were virally suppressed on a regimen of ART containing tenofovir and efavirenz. Immune phenotypes differed significantly between PWH with and without hypertension. The cytokines interleukin-6 and interleukin-17 were elevated in hypertensive PWH compared with those without hypertension. In PWH with hypertension, CD4 T cells expressed less of the activation marker CD38. Markers of macrophage activation and migration were also elevated in hypertensive PWH, including soluble CD163, intracellular adhesion molecule 1, vascular cellular adhesion marker, MIP-1a (macrophage inflammatory protein1a), and MCP-1 (monocyte chemoattractant protein 1). In a surprise finding, hypertensive PWH also had more eosinophils than PWH without hypertension, both by absolute number and by percentage. This association between hypertension and eosinophilia remained statistically significant even after adjusting for age, sex, and fat mass index, as measured by full-body dual-energy X-ray absorptiometry scans. Correspondingly, PWH with hypertension exhibited higher levels of the eosinophil maturation marker interleukin-5, although this did not remain significant in multivariable analyses. To further explore this association between eosinophils and hypertension, Masenga and colleagues investigated a group of 50 HIV-uninfected adults. In this group, hypertension was also associated with higher eosinophil counts; however, the relationship between hypertension and eosinophil could be explained by the higher body mass index in participants without hypertension. Combining these results with existing evidence, Masenga et al hypothesize a new mechanistic pathway for hypertension in PWH. Both HIV and ART are well known to cause endothelial dysfunction. Endothelial dysfunction with release of intracellular adhesion molecule 1 and vascular cellular adhesion marker could induce monocyte activation, which has been observed in some, but not all, reports of hypertension in PWH. These activated macrophages might then produce MIP-1a to activate eosinophils. In addition, activated macrophages and dendritic cells may be the source of interleukin-6, which has been reported to precede and predict hypertension in PWH. Interleukin-6 may, in turn, induce the T-cell–mediated release of interleukin-17, a cytokine associated with hypertension in at least one other study in PWH; it is also known to contribute to hypertension. The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association. From the Center for Global Health, Weill Cornell Medical College, New York, NY; Department of Medicine, Weill Bugando School of Medicine, Mwanza, Tanzania; and Mwanza Interventional Trials Unit, Mwanza, Tanzania. Correspondence to: Robert N. Peck, MD, PhD, Center for Global Health, Weill Cornell Medical College, 402 E 67 St, Floor 2, New York, NY 10021. E-mail: rnp2002@med.cornell.edu J Am Heart Assoc. 2020;9:e015725. DOI: 10.1161/JAHA.120.015725. a 2020 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.