Anticytomegalovirus CD4
            <sup>+</sup>
            T Cells Are Associated With Subclinical Atherosclerosis in Persons With HIV

Wanjalla, Celestine N.; Mashayekhi, Mona; Bailin, Samuel; Gabriel, Curtis L.; Meenderink, Leslie M.; Temu, Tecla M; Fuller, Daniella T; Guo, Liang; Kawai, Kenji; Virmani, Renu; Jenkins, Cathy A.; Abana, Chike O.; Warren, Christian M.; Gangula, Rama; Smith, Rita M.; Madhur, Meena S; Finn, Aloke V.; Gelbard, Alexander; Su, Yan; Tyska, Matthew J.; Kalams, Spyros A.; Harrison, David G.; Mallal, S.; Absi, Tarek; Beckman, Joshua A.; Koethe, John R.

doi:10.1161/atvbaha.120.315786

Cited by 11 publications

(20 citation statements)

References 52 publications

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“…Residual cardiovascular risk in PWH after adjustment for CVD risk is thought to be caused by multiple factors including inflammation. 28 , 30 A persistent HIV viral reservoir, its effect on CD4 T‐cell counts, and other chronic viral co‐infections may be important. The relationships between mean corCSA, ART duration, and CD4 T cells suggest that HIV status and the effect of the virus on CD4 T cells may contribute to coronary arterial remodeling in PWH and CVD risk.…”

Section: Discussionmentioning

confidence: 99%

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Mean Coronary Cross‐Sectional Area as a Measure of Arterial Remodeling Using Noncontrast CT Imaging in Persons With HIV

Werede

Terry

Nair

et al. 2022

JAHA

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Background Persons with HIV have a higher prevalence of coronary artery disease compared with their HIV‐negative counterparts. Earlier identification of subclinical atherosclerosis may provide a greater opportunity for cardiovascular disease risk reduction. We investigated coronary cross‐sectional area (CorCSA) by noncontrasted computed tomography imaging as a noninvasive measure of arterial remodeling among virally suppressed persons with HIV. Methods and Results We assessed 105 persons with HIV with a spectrum of cardiometabolic health. All participants underwent computed tomography imaging to assess the mean corCSA of the proximal left anterior descending artery and 28 participants underwent additional coronary computed tomography angiography. Partial Spearman rank correlations adjusted for cardiovascular disease risk factors were used to assess relationships of corCSA with anthropometric measurements, HIV‐related factors, and plasma cytokines. Mean corCSA measured by noncontrast computed tomography and coronary computed tomography angiography were strongly correlated (ρ=0.91, P <0.0001). Higher mean corCSA was present in those with coronary artery calcium ( P =0.005) and it correlated with participants' atherosclerotic cardiovascular disease risk score (ρ=0.35, P =0.01). After adjusting for established cardiovascular disease risk factors, we observed an inverse relationship between corCSA and CD4 + T‐cell count (ρ=−0.2, P =0.047). Removal of age from the model strengthened the relationships between corCSA and antiretroviral therapy duration (from ρ=0.19, P =0.08 to ρ=0.3, P =0.01). CorCSA was also inversely correlated with plasma IL‐10 (ρ=−0.25, P =0.03) but had no relationship with IL‐6 (ρ=0.11, P =0.4) or IL‐1β (ρ=0.08, P =0.5). Conclusions Positive coronary arterial remodeling, an imaging marker of subclinical atherosclerosis, is associated with a lower CD4 T‐cell count, lower circulating IL‐10, and possibly a longer antiretroviral therapy duration in persons with HIV. Registration Clinicaltrials.gov; Unique identifier: NCT04451980.

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Section: Discussionmentioning

confidence: 99%

“…All plasma cytokines were measured using a standard multiple immunoassay panel (MesoScale, Rockville, MD) as previously published. 28 …”

Section: Methodsmentioning

confidence: 99%

Mean Coronary Cross‐Sectional Area as a Measure of Arterial Remodeling Using Noncontrast CT Imaging in Persons With HIV

Werede

Terry

Nair

et al. 2022

JAHA

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“…CMV is a herpesvirus that co-evolved with mammals and infects many individuals at a young age, and CMV is highly prevalent in some groups including adult PWH (14,15). Growing evidence suggests that anti-CMV T cell responses have a role in metabolic dysregulation in both animal models (16) and humans (17)(18)(19)(20)(21)(22). CMV-seropositivity has been shown to predict severe non-AIDSrelated illnesses and is an independent risk factor for cardiovascular and cerebrovascular disease in PWH (8,23,24).…”

Section: Introductionmentioning

confidence: 99%

“…Prior studies from our group suggest that an increase in CMVspecific CD4 + T cells in PWH may serve as a novel marker of metabolic and cardiovascular disease risk. We previously showed that adipose tissue CD4 + T cells co-expressing CX3CR1, GPR56, and CD57 (termed 'CGC + ' cells), a surface marker combination suggestive of antiviral activity, increased with progressive glucose intolerance (26) and with carotid plaque burden in PWH (18). Furthermore, we showed that CMV-specific CD4 + T cells that recognized an immunodominant peptide epitope (DYSNTHSTRYV from glycoprotein B (gB)) restricted through HLA-DR7 were predominantly CGC + (17,18).…”

Section: Introductionmentioning

confidence: 99%

“…We previously showed that adipose tissue CD4 + T cells co-expressing CX3CR1, GPR56, and CD57 (termed 'CGC + ' cells), a surface marker combination suggestive of antiviral activity, increased with progressive glucose intolerance (26) and with carotid plaque burden in PWH (18). Furthermore, we showed that CMV-specific CD4 + T cells that recognized an immunodominant peptide epitope (DYSNTHSTRYV from glycoprotein B (gB)) restricted through HLA-DR7 were predominantly CGC + (17,18). Further, we demonstrated that CGC + CD4 + T cells were cytotoxic and oligoclonal (17).…”

Section: Introductionmentioning

confidence: 99%

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CD4+ T cells expressing CX3CR1, GPR56, with variable CD57 are associated with cardiometabolic diseases in persons with HIV

et al. 2023

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Persons with HIV (PWH) on long-term antiretroviral therapy (ART) have a higher incidence and prevalence of cardiometabolic diseases attributed, in part, to persistent inflammation despite viral suppression. In addition to traditional risk factors, immune responses to co-infections such as cytomegalovirus (CMV) may play an unappreciated role in cardiometabolic comorbidities and offer new potential therapeutic targets in a subgroup of individuals. We assessed the relationship of CX3CR1+, GPR56+, and CD57+/- T cells (termed CGC+) with comorbid conditions in a cohort of 134 PWH co-infected with CMV on long-term ART. We found that PWH with cardiometabolic diseases (non-alcoholic fatty liver disease, calcified coronary arteries, or diabetes) had higher circulating CGC+CD4+ T cells compared to metabolically healthy PWH. The traditional risk factor most correlated with CGC+CD4+ T cell frequency was fasting blood glucose, as well as starch/sucrose metabolites. While unstimulated CGC+CD4+ T cells, like other memory T cells, depend on oxidative phosphorylation for energy, they exhibited higher expression of carnitine palmitoyl transferase 1A compared to other CD4+ T cell subsets, suggesting a potentially greater capacity for fatty acid β-oxidation. Lastly, we show that CMV-specific T cells against multiple viral epitopes are predominantly CGC+. Together, this study suggests that among PWH, CGC+ CD4+ T cells are frequently CMV-specific and are associated with diabetes, coronary arterial calcium, and non-alcoholic fatty liver disease. Future studies should assess whether anti-CMV therapies could reduce cardiometabolic disease risk in some individuals.

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Cytokine and chemokine receptor profiles in adipose tissue vasculature unravel endothelial cell responses in HIV

Obare,

Priest,

Ismail

et al. 2024

Journal Cellular Physiology

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Chronic systemic inflammation significantly increases myocardial infarction risk in people living with HIV (PLWH). Endothelial cell dysfunction disrupts vascular homeostasis regulation, increasing the risk of vasoconstriction, inflammation, and thrombosis, contributing to cardiovascular disease. We aimed to characterize endothelial cell (EC) chemokines, cytokine, and chemokine receptors of PLWH, hypothesizing that in our cohort, glucose intolerance contributes to their differential expression implicated in endothelial dysfunction. Using single‐cell transcriptomic analysis, we phenotyped chemokine and cytokine receptor expression on arterial ECs, capillary ECs, venous ECs, and vascular smooth muscle cells (VSMCs) in subcutaneous adipose tissue of 59 PLWH with and without glucose intolerance. Our results show that arterial and capillary ECs express significantly higher interferon and tumor necrosis factor (TNF) receptors than venous ECs and VSMCs. Venous ECs exhibited more interleukin (IL)1R1 and ACKR1 receptors, and VSMCs showed significant IL6R expression than arterial and capillary ECs. When stratified by group, arterial ECs from PLWH with glucose intolerance expressed significantly higher IL1R1, IL6R, CXCL12, CCL14, and ICAM2 transcripts than arterial ECs from PLWH without diabetes. Of the different vascular cell types studied, arterial ECs as a proportion of all ECs in adipose tissue were positively correlated with plasma fasting blood glucose. In contrast, venous ECs and VSMCs were positively correlated with plasma IL6. To directly assess the effect of plasma from PLWH on endothelial function, we cultured human arterial ECs (HAECs) in plasma‐conditioned media from PLWH and performed bulk RNA sequencing. Plasma from PLWH stimulated ECs with the upregulation of genes that enrich for the oxidative phosphorylation and the TNF‐α via NFK‐β pathways. In conclusion, ECs in PLWH show heterogeneous cytokine and chemokine receptor expression, and arterial ECs were the most influenced by glucose intolerance. Further research must explicate cytokine and chemokine roles in EC dysfunction and identify biomarkers for disease progression and therapeutic response.

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Anticytomegalovirus CD4 ⁺ T Cells Are Associated With Subclinical Atherosclerosis in Persons With HIV

Cited by 11 publications

References 52 publications

Mean Coronary Cross‐Sectional Area as a Measure of Arterial Remodeling Using Noncontrast CT Imaging in Persons With HIV

Mean Coronary Cross‐Sectional Area as a Measure of Arterial Remodeling Using Noncontrast CT Imaging in Persons With HIV

CD4+ T cells expressing CX3CR1, GPR56, with variable CD57 are associated with cardiometabolic diseases in persons with HIV

Cytokine and chemokine receptor profiles in adipose tissue vasculature unravel endothelial cell responses in HIV

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Anticytomegalovirus CD4 + T Cells Are Associated With Subclinical Atherosclerosis in Persons With HIV

Cited by 11 publications

References 52 publications

Mean Coronary Cross‐Sectional Area as a Measure of Arterial Remodeling Using Noncontrast CT Imaging in Persons With HIV

Mean Coronary Cross‐Sectional Area as a Measure of Arterial Remodeling Using Noncontrast CT Imaging in Persons With HIV

CD4+ T cells expressing CX3CR1, GPR56, with variable CD57 are associated with cardiometabolic diseases in persons with HIV

Cytokine and chemokine receptor profiles in adipose tissue vasculature unravel endothelial cell responses in HIV

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Anticytomegalovirus CD4 ⁺ T Cells Are Associated With Subclinical Atherosclerosis in Persons With HIV