Monocytes as Regulators of Inflammation and HIV-Related Comorbidities during cART

Anzinger, Joshua J.; Butterfield, Tiffany R; Angelovich, Thomas A; Crowe, Suzanne; Palmer, Clovis S.

doi:10.1155/2014/569819

Cited by 86 publications

(86 citation statements)

References 122 publications

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“…Over-activation of monocytes/macrophages profoundly contributes to systemic inflammation and BBB damage in HIV-1 patients, leading to HIV-1-associated neuropathogenesis (Anzinger et al, 2014; Gras and Kaul, 2010; Kim et al, 2005). The levels of sCD14 and sCD163 have been used as reliable markers of monocytes/macrophage activation and systemic inflammation in HIV-1 patients (Brenchley et al, 2006; Burdo et al, 2011a,b).…”

Section: Resultsmentioning

confidence: 99%

“…Studies have demonstrated that activated monocytes/macrophages orchestrate these events and play a central role in BBB injury in HIV-1 patients (Anzinger et al, 2014; Gras and Kaul, 2010; Kim et al, 2005). Activated monocytes/macrophages increase the production of MMPs and inflammatory cytokines, enhance infiltration of inflammatory cells and HIV-1-infected cells into the CNS, and accelerate the influx of neurotoxic substances into the brain, thereby promoting HIV-1-associated neuropathogenesis (Anzinger et al, 2014; Gras and Kaul, 2010; Kim et al, 2005). Along these lines, we measured circulating levels of sCD14 and sCD163, two markers of monocyte/macrophage activation and inflammation (Brenchley et al, 2006; Burdo et al, 2011a,b), in the plasma from HIV-1 patients and HD individuals.…”

Section: Discussionmentioning

confidence: 99%

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MMPs/TIMPs imbalances in the peripheral blood and cerebrospinal fluid are associated with the pathogenesis of HIV-1-associated neurocognitive disorders

Xing

Shepherd

Lan

et al. 2017

Brain, Behavior, and Immunity

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HIV-1-associated neurocognitive disorders (HAND) continue to be a major concern in the infected population, despite the widespread use of combined antiretroviral therapy (cART). Growing evidence suggests that an imbalance between matrix metalloproteinases (MMPs) and endogenous tissue inhibitors of MMPs (TIMPs) contributes to the pathogenesis of HAND. In our present study, we examined protein levels and enzymatic activities of MMPs and TIMPs in both plasma and cerebrospinal fluid (CSF) samples from HIV-1 patients with or without HAND and HIV-1-negative controls. Imbalances between MMPs and TIMPs with distinct patterns were revealed in both the peripheral blood and CSF of HIV-1 patients, especially those with HAND. In the peripheral blood, the protein levels of MMP-2, MMP-9, TIMP-1, TIMP-2, and the enzymatic activities of MMP-2 and MMP-9 were increased in HIV-1 patients with or without HAND when compared with HIV-1-negative controls. The enzymatic activity of MMP-2, but not MMP-9, was further increased in plasma samples of HAND patients than that of HIV-1 patients without HAND. Notably, the ratio of MMP-2/TIMP-2 in plasma was significantly increased in HAND patients, not in patients without HAND. In the CSF, MMP-2 activity was increased, but the ratio of MMP-2/TIMP-2 was not altered. De novo induction and activation of MMP-9 in the CSF of HAND patients was particularly prominent. The imbalances between MMPs and TIMPs in the blood and CSF were related to the altered profiles of inflammatory cytokines/chemokines and monocyte activation in these individuals. In addition, plasma from HIV-1 patients directly induced integrity disruption of an in vitro blood-brain barrier (BBB) model, leading to increased BBB permeability and robust transmigration of monocytes/-macrophages. These results indicate that imbalances between MMPs and TIMPs are involved in BBB disruption and are implicated in the pathogenesis of neurological disorders such as HAND in HIV-1 patients.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

MMPs/TIMPs imbalances in the peripheral blood and cerebrospinal fluid are associated with the pathogenesis of HIV-1-associated neurocognitive disorders

Xing

Shepherd

Lan

et al. 2017

Brain, Behavior, and Immunity

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“…Immune stimuli present during HIV infection, such as the microbial translocation product LPS, can activate monocytes [26], causing an upregulation of GLUT1 [26,27]. Although we did not examine the cause of differential intermediate monocyte GLUT1 expression for the two IMT groups in this study, it is possible that increased levels of monocyte stimuli in some HIV-infected persons could lead to increased monocyte activation and GLUT1 expression [28,29].…”

Section: Discussionmentioning

confidence: 99%

Increased glucose transporter-1 expression on intermediate monocytes from HIV-infected women with subclinical cardiovascular disease

Butterfield

Hanna²,

Kaplan³

et al. 2017

Aids

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Objective People living with HIV (PLWH) have chronic immune activation and increased cardiovascular disease (CVD) risk. Activation of monocytes and T lymphocytes causes up-regulation of glucose transporter-1 (GLUT1) for efficient function. PLWH have an increased percentage of GLUT1-expressing monocytes and T lymphocytes, but it is unclear if these cells are associated with CVD. We evaluated expression of GLUT1 and CD38 on monocyte and T lymphocyte populations from HIV-infected women with subclinical CVD. Methods Participants with >75th percentile (n=15) and <25th percentile (n=15) age-adjusted intima-media thickness (IMT) at the right common carotid artery and bifurcation were identified from the Women's Interagency HIV Study. Groups were matched by age, race/ethnicity, smoking status, and CD4 count. All women were receiving suppressive antiretroviral therapy except for one high and one low IMT participant. Monocyte and T lymphocyte populations were evaluated for GLUT1 and CD38 expression using flow cytometry. Results Intermediate monocytes from high IMT women had significantly increased expression of GLUT1 (310 MFI vs. 210 MFI, p=0.024) (66.4% vs. 48.5%, p=0.031) and CD38 (339 MFI vs. 211 MFI, p=0.002) (10.5% vs. 3.8%, p=0.0002) compared to women with low IMT. High and low IMT participants showed no differences in GLUT1 or CD38 expression on classical monocytes, non-classical monocytes, CD4+ and CD8+ T lymphocytes. Conclusion GLUT1-expressing intermediate monocytes are elevated in HIV-infected women with subclinical CVD. These cells may contribute to development of CVD in PLWH and could be a novel target to limit inflammation.

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“…[46][47][48] With chronic inflammation, there are increased comorbidities, compared to the general non-HIVinfected population. [49][50][51] In particular, there is an increased incidence of CVD 4 where monocytes/macrophages are increasingly considered to play a role. 52,53 Previously, we have shown that SIV-infected, CD8-lymphocyte-depleted monkeys have increased numbers of macrophages (CD163 + , CD68 + , and MAC387 + ) in cardiac tissues that positively correlate increased fibrosis.…”

Section: Discussionmentioning

confidence: 99%

Anti‐α4 Integrin Antibody Blocks Monocyte/Macrophage Traffic to the Heart and Decreases Cardiac Pathology in a SIV Infection Model of AIDS

Walker

Beck

Campbell

et al. 2015

JAHA

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BackgroundCardiovascular disease (CVD), myocarditis and fibrosis are comorbidities of HIV+ individuals on durable antiretroviral therapy (ART). Although mechanisms for these vary, monocytes/macrophages are increasingly demonstrated to be key players.Methods and ResultsWe directly blocked monocyte/macrophage traffic to the heart in an SIV model of AIDS using an anti-alpha-4 integrin antibody (natalizumab). Nineteen Rhesus macaques were SIVmac251 infected and CD8-lymphocyte depleted for the development of rapid AIDS. Ten animals received natalizumab once a week, for 3 weeks, and were sacrificed 1 week later. Six animals began treatment at the time of infection (early) and the remaining 4 began treatment 28 days post-infection (late), a time point we have previously established when significant cardiac inflammation occurs. Nine animals were untreated controls; of these, 3 were sacrificed early and 6 were sacrificed late. At necropsy, we found decreased SIV-associated cardiac pathology in late natalizumab-treated animals, compared to untreated controls. Early and late treatment resulted in significant reductions in numbers of CD163+ and CD68+ macrophages in cardiac tissues, compared to untreated controls, and a trend in decreasing numbers of newly recruited MAC387+ and BrdU+ (recruited) monocytes/macrophages. In late treated animals, decreased macrophage numbers in cardiac tissues correlated with decreased fibrosis. Early and late treatment resulted in decreased cardiomyocyte damage.ConclusionsThese data demonstrate a role for macrophages in the development of cardiac inflammation and fibrosis, and suggest that blocking monocyte/macrophage traffic to the heart can alleviate HIV- and SIV-associated myocarditis and fibrosis. They underscore the importance of targeting macrophage activation and traffic as an adjunctive therapy in HIV infection.

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Monocytes as Regulators of Inflammation and HIV-Related Comorbidities during cART

Cited by 86 publications

References 122 publications

MMPs/TIMPs imbalances in the peripheral blood and cerebrospinal fluid are associated with the pathogenesis of HIV-1-associated neurocognitive disorders

MMPs/TIMPs imbalances in the peripheral blood and cerebrospinal fluid are associated with the pathogenesis of HIV-1-associated neurocognitive disorders

Increased glucose transporter-1 expression on intermediate monocytes from HIV-infected women with subclinical cardiovascular disease

Anti‐α4 Integrin Antibody Blocks Monocyte/Macrophage Traffic to the Heart and Decreases Cardiac Pathology in a SIV Infection Model of AIDS

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