Lauren Stone

Application of a Novel CD206+ Macrophage-Specific Arterial Imaging Strategy in HIV-Infected Individuals

Background The ability to noninvasively assess arterial CD206+ macrophages may lead to improved understanding of human immunodeficiency virus (HIV)-associated cardiovascular disease. Methods We trialed a novel macrophage-specific arterial imaging technique. Results We demonstrated colocalization between technetium Tc 99m tilmanocept (99mTc-tilmanocept) and CD206+ macrophages ex vivo. In vivo application of 99mTc-tilmanocept single-photon emission computed tomography/computed tomography revealed high-level 99mTc-tilmanocept uptake across 20.4% of the aortic surface volume among HIV-infected subjects, compared with 4.3% among non-HIV-infected subjects (P = .009). Among all subjects, aortic high-level 99mTc-tilmanocept uptake was related to noncalcified aortic plaque volume (r = 0.87; P = .003) on computed tomographic angiography, and this relationship held when we controlled for HIV status. Conclusion These first-in-human data introduce a novel macrophage-specific arterial imaging technique in HIV. Clinical Trials Registration NCT02542371.

Does effort influence inequity aversion in cotton-top tamarins (Saguinus oedipus)?

The human sense of fairness entails sensitivity not just to equality, the equal division of resources, but also to merit, the relationship between an individual’s share of resources and how hard they worked for their share. Recent evidence suggests that our sensitivity to equality has deep phylogenetic roots: several nonhuman animal species show an aversion to unequal reward distributions. However, the extent to which nonhuman animals share sensitivity to merit remains poorly understood, largely because previous studies have failed to properly manipulate work effort in inequity aversion tasks. Here, we tested whether cotton-top tamarins (Saguinus oedipus) would exhibit a differential response to inequity when acquiring rewards was either (1) effortful or (2) effortless. Subjects engaged in a pulling task in which they had an opportunity to deliver a disadvantageously unequal distribution of food to themselves and a partner (one piece for self, four pieces for partner). We made delivery effortful by adding a weight to the pulling handle. Critically, effort was calibrated to each individual. Results show that individuals varied markedly in their response to effort, highlighting the importance of manipulating work effort at the individual level. Overall, subjects showed little aversion to inequity. However, subjects were slightly less likely to accept inequity when doing so was effortful, although this effect was pronounced in only one individual. Our findings suggest a new method for capturing individual variation in effort and for studying the roots of the concept of merit in nonhuman animals.

Cardiovascular disease risk among women living with HIV in North America and Europe

Purpose of review To examine the epidemiology and mechanistic underpinnings of heightened cardiovascular disease (CVD) risk among women living with HIV (WLHIV) in North America and Europe. Recent findings WLHIV in North America and Europe exhibit high CVD incidence rates, which are at par with those of compatriot men living with HIV. Compared with uninfected women, WLHIV in these regions face a 2–4-fold increased relative risk for myocardial infarction, stroke, and heart failure. HIV-associated CVD risk is fuelled by a negative synergy of traditional cardiometabolic risk factors and heightened systemic immune activation/inflammation. Among WLHIV, female sex and endogenous sex hormone production influence both traditional cardiometabolic risk factors and patterns of systemic immune activation/inflammation. WLHIV in North America and Europe may also experience heightened CVD risk in relation to a relatively increased prevalence of behavioral and psychosocial CVD risk factors, coupled with suboptimal therapeutic targeting of known traditional cardiometabolic risk factors. Summary Additional research on sex-specific mechanisms of HIV-associated CVD – based not only out of North America and Europe but also and especially out of Africa, Asia, and South America – will inform the development of CVD prediction algorithms and prevention guidelines clinically relevant to the approximately 17 million women aging with HIV globally.

Yearning and Its Measurement in Complicated Grief

ABSTRACT Persistent intense yearning for the deceased is a core clinical feature of complicated grief (CG) that distinguishes it from other mental disorders that develop following loss. The Yearning in Situations of Loss Scale (YSL) is a recently developed assessment of yearning. To assess the psychometric properties of the YSL in those with CG, we administered the YSL, Inventory of Complicated Grief, and Quick Inventory of Depression Symptomatology to 303 treatment-seeking bereaved adults with CG. Our results suggest the YSL is a reliable assessment with acceptable convergent and discriminant validity as a measure of yearning in those with CG.

HDL Cholesterol Efflux Capacity in Newly Diagnosed HIV and Effects of Antiretroviral Therapy

Context: In the general population, high‐density lipoprotein (HDL) cholesterol efflux capacity (HCEC) relates inversely to incident cardiovascular events. Previous studies have suggested that HCEC is decreased in HIV and that antiretroviral therapy (ART) initiation might improve HCEC. Objective: To evaluate HCEC in the context of ART initiation and immune activation in HIV. Design and Outcome Measures: Baseline HCEC from 10 ART‐naive HIV‐infected males and 12 prospectively matched non‐HIV‐infected males were analyzed. In the HIV cohort, HCEC 6 months after elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (E/C/F/TDF) therapy was evaluated. HCEC served as the primary outcome and was measured by the ability of J774 mouse macrophages to efflux cholesterol. Our ex vivo assay used two cholesterol acceptors [apolipoprotein B (apoB)‐depleted sera or purified HDL] and modulation of cellular efflux pathways using a liver X receptor (LXR) agonist. Results: The median age was 34 years [interquartile range (IQR), 27 to 51], and baseline HDL was 46 mg/dL (IQR, 38 to 61). HCEC was significantly greater in the non‐HIV‐infected subjects than in the HIV‐infected subjects at baseline. HCEC, assessed using apoB‐depleted sera, significantly increased after ART (no LXR agonist, baseline: median, 8.1%; IQR, 7.0% to 11.9%; after ART: median, 12.9%; IQR, 10.4% to 21.1%; P = 0.006; LXR agonist, baseline, 1.3% ± 1.3%; after ART, 2.5% ± 1.0%; P = 0.02), although not to the levels in the non‐HIV‐infected subjects (no LXR agonist: median, 14.9%; IQR, 11.5% to 19.1%; LXR agonist: 5.8% ± 1.3%). HCEC, assessed using purified HDL, did not significantly increase after ART. The change in HCEC with ART related inversely to the change in the percentage of CD14−CD16+ (nonclassical) monocytes (&rgr; = −0.74, P = 0.04) and directly to the change in the percentage of CD14+CD16− (classical) monocytes (&rgr; = 0.72, P = 0.045). Conclusions: Our data suggest improvement of HCEC with E/C/F/TDF and a relationship between the ART‐induced decrease in immune activation and ART‐induced improvement in HCEC.

Assessing statin effects on cardiovascular pathways in HIV using a novel proteomics approach: Analysis of data from INTREPID, a randomized controlled trial

Background People with HIV (PWH) demonstrate increased cardiovascular disease (CVD), due in part to increased immune activation, inflammation, and endothelial dysfunction. Methods In a randomized trial (INTREPID), 252 HIV-infected participants with dyslipidemia and no history of coronary artery disease were randomized (1:1) to pitavastatin 4 mg vs. pravastatin 40 mg for 52 weeks. Using a proteomic discovery approach, 92 proteins biomarkers were assessed using Proximity Extension Assay technology to determine the effects of statins on key atherosclerosis and CVD pathways among PWH. 225 participants had specimens available for biomarker analysis pre- and post-baseline. Findings The mean age was 49.5 ± 8.0 (mean ± SD), LDL-C 155 ± 25 mg/dl and CD4 count 620 ± 243 cell/mm3. Among all participants, three proteins significantly decreased: tissue factor pathway inhibitor [TFPI; t-statistic = −6.38, FDR p-value<0.0001], paraoxonase 3 [PON3; t-statistic = −4.64, FDR p-value = 0.0003], and LDL-receptor [LDLR; t-statistic = −4.45, FDR p-value = 0.0004]; and two proteins significantly increased galectin-4 [Gal-4; t-statistic = 3.50, FDR p-value = 0.01] and insulin-like growth factor binding protein 2 [IGFBP-2; t-statistic = 3.21, FDR p-value = 0.03]. The change in TFPI was significantly different between the pitavastatin and pravastatin groups. Among all participants, change in TFPI related to the change in LDL-C (r = 0.43, P < 0.0001) and change in Lp-PLA2 (r = 0.29, P < 0.0001). Interpretation Using a proteomics approach, we demonstrated that statins led to a significant reduction in the levels of TFPI, PON3, and LDLR and an increase in Gal-4 and IGFBP-2, key proteins involved in coagulation, redox signaling, oxidative stress, and glucose metabolism. Pitavastatin led to a greater reduction in TFPI than pravastatin. These data highlight potential novel mechanisms of statin effects among PWH. Fund This work was supported by an investigator-initiated grant to S.K.G. from KOWA Pharmaceuticals America, Inc. and the National Institutes of Health [P30 DK040561; Nutrition Obesity Research Center at Harvard]. M.T. was support by National Institutes of Health [5KL2TR001100-05; Harvard Catalyst KL2 grant].

Proprotein Convertase Subtilisin/Kexin 9 Levels in Relation to Systemic Immune Activation and Subclinical Coronary Plaque in HIV

Abstract Background Proprotein convertase subtilisin/kexin 9 (PCSK9) is known to mediate homeostasis of low-density lipoprotein cholesterol (LDL-c), but it may also participate in immune reactivity and atherogenesis. Methods We compared circulating PCSK9 levels among asymptomatic individuals with and without HIV. Further, within each group, we assessed the relationship between PCSK9 levels, traditional cardiovascular disease risk factors, immune activation, and subclinical coronary atherosclerotic plaque. Results PCSK9 levels were higher among HIV-infected (n = 149) vs matched non-HIV-infected subjects (n = 69; 332 [272, 412] ng/mL vs 304 [257, 375] ng/mL; P = .047). Among HIV-infected subjects, significant albeit modest positive associations were noted between PCSK9 levels and markers of systemic monocyte activation including sCD14 (rho = 0.22; P = .009) and sCD163 (rho = 0.23; P = .006). In this group, PCSK9 levels related weakly to LDL-c (rho = 0.16; P = .05) and also to Framingham Point Score but did not relate to subclinical coronary atherosclerotic plaque parameters. Conclusions Among HIV-infected individuals, circulating PCSK9 levels are elevated and related to systemic markers of monocyte activation but not to coronary plaque parameters. Additional studies are needed to determine the effects of PCSK9 on immune activation and atherogenesis in HIV and to assess whether PCSK9 inhibition reduces immune activation and coronary atherosclerotic plaque burden. Clinical Trial Registration NCT00455793.