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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.

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 longterm 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 boxidation. 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. [ABSTRACT FROM AUTHOR]

Summary: CD8α+ dendritic cells (DCs) are important in vivo for cross-presentation of antigens derived from intracellular pathogens and tumors. Additionally, secretion of interleukin-12 (IL-12) by CD8α+ DCs suggests a role for these cells in response to Toxoplasma gondii antigens, although it remains unclear whether these cells are required for protection against T. gondii infection. Toward this goal, we examined T. gondii infection of Batf3 −/− mice, which selectively lack only lymphoid-resident CD8α+ DCs and related peripheral CD103+ DCs. Batf3 −/− mice were extremely susceptible to T. gondii infection, with decreased production of IL-12 and interferon-γ. IL-12 administration restored resistance in Batf3−/− mice, and mice in which IL-12 production was ablated only from CD8α+ DCs failed to control infection. These results reveal that the function of CD8α+ DCs extends beyond a role in cross-presentation and includes a critical role for activation of innate immunity through IL-12 production during T. gondii infection. [ABSTRACT FROM AUTHOR]

An increased risk of cardiometabolic disease accompanies persistent systemic inflammation. Yet, the innate and adaptive immune system features in persons who develop these conditions remain poorly defined. Doublets, or cell-cell complexes, are routinely eliminated from flow cytometric and other immune phenotyping analyses, which limits our understanding of their relationship to disease states. Using well-characterized clinical cohorts, including participants with controlled HIV as a model for chronic inflammation and increased immune cell interactions, we show that circulating CD14 + monocytes complexed to CD3 + T cells are dynamic, biologically relevant, and increased in individuals with diabetes after adjusting for confounding factors. The complexes form functional immune synapses with increased expression of proinflammatory cytokines and greater glucose utilization. Furthermore, in persons with HIV, the CD3 + T-cell: CD14 + monocyte complexes had more HIV copies compared to matched CD14 + monocytes or CD4 + T cells alone. Our results demonstrate that circulating CD3 + T-cell:CD14 + monocyte pairs represent dynamic cellular interactions that may contribute to inflammation and cardiometabolic disease pathogenesis and may originate or be maintained, in part, by chronic viral infections. These findings provide a foundation for future studies investigating mechanisms linking T cellmonocyte cell-cell complexes to developing immune-mediated diseases, including HIV and diabetes., Competing Interests: Declaration of interests The authors have no competing interests.

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Wanjalla, Gabriel, Fuseini, Bailin, Mashayekhi, Simmons, Warren, Glass, Oakes, Gangula, Wilfong, Priest, Temu, Newell, Pakala, Kalams, Gianella, Smith, Harrison, Mallal and Koethe.)

Objective: Fat redistribution from subcutaneous adipose tissue (SAT) to the abdominal viscera, pericardium, liver, and skeletal muscle contributes to the rising burden of cardiometabolic disease among persons with HIV (PWH). Previous studies found SAT inflammation in PWH impairs lipid storage and persists despite plasma viral suppression on antiretroviral therapy (ART). In this study, we identified SAT immune-related genes associated with ectopic fat deposition in PWH on long-term ART., Design and Methods: A total of 92 PWH with well-controlled viremia underwent computed tomography imaging and abdominal SAT biopsy for gene expression analysis. SAT gene expression was measured using a NanoString panel of 255 immune-related genes. Associations between gene expression and computed tomography measurements of the volume and attenuation (radiodensity) of metabolically relevant ectopic fat depots were assessed using multivariable linear regression and network analysis., Results: Greater SAT volume was associated with higher visceral and pericardial adipose tissue volume, but lower skeletal muscle attenuation. Lower SAT attenuation, a measure of lipid content, was associated with lower visceral adipose tissue attenuation. Hierarchical clustering identified a subset of macrophage-related genes in SAT, including CCL2, CCL22, CCL13, CCR1, CD86, CD163, IL-6, IL-10, MRC1, and TREM2, which were associated with an increased lipid deposition in multiple ectopic depots., Conclusion: Altered expression of macrophage-related genes in SAT is associated with differences in ectopic fat depot morphometrics among PWH on long-term ART, including in the pericardial and visceral compartments. These findings provide basis for future studies to assess host, virus, and treatment factors shaping the SAT immune environment and its effects on morphometric changes and metabolic comorbidities in PWH., Competing Interests: J.R.K. has served as a consultant to Gilead Sciences, Merck, ViiV Healthcare, Janssen, and Theratechnologies and has received research support from Gilead Sciences and Merck. C.N.W. has served as a consultant to ViiV Healthcare. J.A.K. has served as a consultant for Boehringer Ingelheim, Janssen, and APIE Therapeutics, received grant support from Boehringer Ingelheim and Bristol-Meyers-Squibb, and other study support from Genentech. S.N., J.G.T., and J.J.C. receive grant support from Theratechnologies and IBM Watson. The remaining authors have no conflicts of interest to disclose., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

While antiretroviral therapy (ART) has proven effective in suppressing viremia and disease progression among people living with human immunodeficiency virus (HIV; PLWH), suboptimal CD4 + T cell reconstitution remains a major obstacle in nearly 30% of ART-treated individuals. Epidemiological studies demonstrate that obesity, or a body mass index (BMI) ≥ 30 kg/m 2 , is positively correlated with greater CD4 + T cell recovery in PLWH on ART. Leptin is a known immunomodulator that is produced in proportion to fat mass and is increased in obese individuals, including PLWH. We hypothesized that CD4 + T cells from obese PLWH have increased cell proliferation and cytokine production compared to cells from lean PLWH, potentially modulated by differential effects of leptin signaling. To test this hypothesis, peripheral blood mononuclear cells from obese and lean PLWH with long-term virologic suppression on the same ART regimen were pretreated with recombinant leptin and then stimulated with anti-CD3/CD28 or PMA/ionomycin to measure Ki67 expression, leptin receptor (LepR) surface expression and cytokine production. In the absence of leptin, Ki67 expression and IL-17A production were significantly higher in CD4 + T cells from obese compared to lean PLWH. However, LepR expression was significantly lower on CD4 + T cells from obese compared to lean PLWH. After leptin treatment, Ki67 expression was significantly increased in CD4 + T cells from obese PLWH compared to the lean participants. Leptin also increased IL-17A production in CD4 + T cells from obese healthy controls. In contrast, leptin decreased IL-17A production in CD4 + T cells from both obese and lean PLWH. Combined, these results demonstrate that obesity is associated with greater CD4 + T cell proliferation among PLWH, and that higher circulating leptin levels in obesity may contribute to improved CD4 + T reconstitution in PLWH initiating ART., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Fuseini, Smith, Nochowicz, Simmons, Hannah, Wanjalla, Gabriel, Mashayekhi, Bailin, Castilho, Hasty, Koethe and Kalams.)

Chronic T cell activation and accelerated immune senescence are hallmarks of HIV infection, which may contribute to the increased risk of cardiometabolic diseases in people living with HIV (PLWH). T lymphocytes play a central role in modulating adipose tissue inflammation and, by extension, adipocyte energy storage and release. Here, we assessed the CD4 + and CD8 + T cell profiles in the subcutaneous adipose tissue (SAT) and blood of non-diabetic ( n = 9; fasting blood glucose [FBG] < 100 mg/dL), pre-diabetic ( n = 8; FBG = 100-125 mg/dL) and diabetic ( n = 9; FBG ≥ 126 mg/dL) PLWH, in addition to non- and pre-diabetic, HIV-negative controls ( n = 8). SAT was collected by liposuction and T cells were extracted by collagenase digestion. The proportion of naïve (T Nai ) CD45RO - CCR7 + , effector memory (T EM ) CD45RO + CCR7 - , central memory (T CM ) CD45RO + CCR7 + , and effector memory revertant RA + (T EMRA ) CD45RO - CCR7 - CD4 + and CD8 + T cells were measured by flow cytometry. CD4 + and CD8 + T EM and T EMRA were significantly enriched in SAT of PLWH compared to blood. The proportions of SAT CD4 + and CD8 + memory subsets were similar across metabolic status categories in the PLWH, but CD4 + T cell expression of the CD69 early-activation and tissue residence marker, particularly on T EM cells, increased with progressive glucose intolerance. Use of t-distributed Stochastic Neighbor Embedding (t-SNE) identified a separate group of predominantly CD69 lo T EM and T EMRA cells co-expressing CD57, CX 3 CR1, and GPR56, which were significantly greater in diabetics compared to non-diabetics. Expression of the CX 3 CR1 and GPR56 markers indicate these T EM and T EMRA cells may have anti-viral specificity. Compared to HIV-negative controls, SAT from PLWH had an increased CD8:CD4 ratio, but the distribution of CD4 + and CD8 + memory subsets was similar irrespective of HIV status. Finally, whole adipose tissue from PLWH had significantly higher expression of TLR2, TLR8, and multiple chemokines potentially relevant to immune cell homing compared to HIV-negative controls with similar glucose tolerance.