Association of Arterial and Lymph Node Inflammation With Distinct Inflammatory Pathways in Human Immunodeficiency Virus Infection

Abstract

Background HIV infection is associated with a high risk of cardiovascular diseases (CVD) and increased arterial inflammation. In HIV, inflammation is also increased within lymph nodes (LN), tissues known to harbor the virus even among treated and suppressed individuals. We tested the hypothesis that arterial inflammation is linked to HIV disease activity and to inflammation within HIV-infected tissues (LN). Methods Seventy-four individuals were studied: 45 HIV-infected individuals and 29 uninfected controls. Arterial and LN inflammation were measured using 18F-fluorodeoxyglucose positron emission tomography, (FDG-PET). Detailed immunophenotyping was performed, along with measurement of viral activity/persistence, and circulating inflammatory biomarkers. Results Median age was 53 years, 100% male. Lymph node inflammation was higher in HIV-infected individuals and correlated with markers of viral disease activity (viral load, CD8+ T cells, CD4/CD8 ratio) and CD4+ T cell activation. Arterial inflammation was modestly increased in HIV-infected individuals and was positively correlated with circulating inflammatory biomarkers (hsCRP, IL-6) and activated monocytes (CD14dimCD16+; non-classical) but not to markers of HIV. While LN and arterial inflammation were increased in HIV, inflammatory activity in these tissues was not related (r=0.09, p=0.56). Conclusion While LN and to a lesser degree, the arterial wall are inflamed in HIV, inflammation in these tissues is not closely linked. Namely, measures of HIV disease activity strongly associate with LN inflammation but not arterial inflammation. These data suggest that LN and arterial inflammation do not share underlying pathways of immune activation and suggests therapeutic interventions that reduce viral disease activity may not predictably reduce arterial inflammation in HIV or its down-stream consequence (CVD).

HIV-1–Associated Atherosclerosis

“…A recent study demonstrated that arterial inflammation in HIV + patients, as measured by 18 F-FDG PET, correlated with CRP, IL-6, and CD14 + CD16 + monocytes, markers of immune activation, whereas LN inflammation correlated with measures of HIV disease activity (58). Another recent report showed discordant effects of newly-initiated ART in treatment-naïve HIV + patients, which restored peripheral immune function, but did not reduce arterial inflammation (59).…”

Caspase-1-associated immune activation in an accelerated SIV-infected rhesus macaque model

“…Previous studies have indicated that ART suppresses inflammation in the circulation, but immune activation may persist in certain tissues in PLWH (Tawakol et al 2017; Zanni et al 2016). Therefore, we further investigated how ART affects SIV-associated caspase-1 pathway activation in the lymph node.…”

“…PLWH now have a life expectancy close to that of the general population; however, they still present with a high prevalence of HIV-associated comorbidities including CVD and HAND (Kearns et al 2017b). Clinical evidence indicates that although ART is able to suppress inflammation in the circulation, immune activation and inflammation may persist in certain tissues (Fitch et al 2013; Tawakol et al 2017; Zanni et al 2016; Pereyra et al 2012). In the context of viral suppression, the underlying molecular mechanisms connecting HIV-associated immune activation to comorbidities remains largely unknown (Kearns et al 2017a).…”

Digital spatial profiling of coronary plaques from persons living with HIV reveals high levels of STING and CD163 in macrophage enriched regions

“…[1][2][3][4][5] Chronic inflammation due to HIV-infection and other viral pathogens such as cytomegalovirus (CMV) and hepatitis C virus, have been linked to accelerated atherosclerosis 6,7 and may in part explain this increased risk. Aortic and carotid artery inflammation measured by 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) imaging, 14,15 showed greater tracer uptake in PLWH and was associated with higher plasma hsCRP, IL-6, CX3CR1 + monocytes, and potentially CX3CR1 + CD4 + T cells. 14 In general, PLWH on ART have higher levels of inflammation compared to HIV-negative persons.…”

“…Aortic and carotid artery inflammation measured by 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) imaging, 14,15 showed greater tracer uptake in PLWH and was associated with higher plasma hsCRP, IL-6, CX3CR1 + monocytes, and potentially CX3CR1 + CD4 + T cells. 14 In general, PLWH on ART have higher levels of inflammation compared to HIV-negative persons. 8,9 Higher levels of circulating interleukin-6 (IL-6), high sensitivity c-reactive protein (hsCRP) and d-dimer are associated with CVD events in PLWH [10][11][12] .…”