Impaired T-cell responses to sphingosine-1-phosphate in HIV-1 infected lymph nodes

Mudd, Joseph C.; Murphy, Patrick S.; Manion, Maura; Debernardo, Robert; Hardacre, Jeffrey M.; Ammori, John B.; Hardy, Gareth; Harding, Clifford V.; Mahabaleshwar, Ganapati; Jain, Mukesh K.; Jacobson, Jeffrey M.; Brooks, Ari D.; Lewis, Sharon L.; Schacker, Timothy W.; Anderson, Jodi; Haddad, Elias K.; Cubas, Rafael; Rodrı́guez, Benigno; Sieg, Scott F.; Lederman, Michael M.

doi:10.1182/blood-2012-07-445783

Cited by 32 publications

(33 citation statements)

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“…The first rapid phase seen in the first few weeks of therapy is thought to be a consequence of systemic redistribution of sequestered lymphocytes from inflamed and activated lymphoid tissues as viral replication is halted (Bucy et al, 1999) while the second slower phase is thought to represent homeostatic CD4+ T cell restoration. We have recently found that LN T cells in untreated HIV infection have an impaired responsiveness to sphingosine-1 phosphate, the phospholipid that mediates chemotactic egress of lymphocytes from lymphoid tissues (Mudd et al, 2013). This defect can be induced in vitro by both T cell receptor engagement and by exposure to type 1 interferons as well as to a variety of microbial toll-like receptor agonists (Mudd et al, 2013).…”

Section: The Ln In Treated Hiv Infectionmentioning

confidence: 99%

“…We have recently found that LN T cells in untreated HIV infection have an impaired responsiveness to sphingosine-1 phosphate, the phospholipid that mediates chemotactic egress of lymphocytes from lymphoid tissues (Mudd et al, 2013). This defect can be induced in vitro by both T cell receptor engagement and by exposure to type 1 interferons as well as to a variety of microbial toll-like receptor agonists (Mudd et al, 2013). Treatment with antiretroviral drugs largely (but not completely) corrects this defect thereby providing a mechanistic explanation for the rapid systemic first-phase CD4+ T cell restoration with ART.…”

Section: The Ln In Treated Hiv Infectionmentioning

confidence: 99%

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Residual Immune Dysregulation Syndrome in Treated HIV infection

Lederman

Funderburg

Sékaly

et al. 2013

Advances in Immunology

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303

273

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Antiretroviral therapy has revolutionized the course of HIV infection, improving immune function and decreasing dramatically the mortality and morbidity due to the opportunistic complications of the disease. Nonetheless, even with sustained suppression of HIV replication, many HIV-infected persons experience a syndrome characterized by increased T cell activation and evidence of heightened inflammation and coagulation. This residual immune dysregulation syndrome or RIDS is more common in persons who fail to increase circulating CD4+ T cells to normal levels and in several epidemiologic studies it has been associated with increased morbidity and mortality. These morbid and fatal events are not the typical opportunistic infections and malignancies seen in the early AIDS era but rather comprise a spectrum of cardiovascular events, liver disease, metabolic disorders, kidney disease, bone disease, and a spectrum of malignant complications distinguishable from the opportunistic malignancies that characterized the earlier days of the AIDS epidemic. While immune activation, inflammation, and coagulopathy are characteristic of untreated HIV infection and improve with drug-induced control of HIV replication, the drivers of RIDS in treated HIV infection are incompletely understood. And while inflammation, immune activation, and coagulopathy are more common in treated persons who fail to restore circulating CD4+ T cells, it is not entirely clear how these two phenomena are linked.

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Section: The Ln In Treated Hiv Infectionmentioning

confidence: 99%

Section: The Ln In Treated Hiv Infectionmentioning

confidence: 99%

Residual Immune Dysregulation Syndrome in Treated HIV infection

Lederman

Funderburg

Sékaly

et al. 2013

Advances in Immunology

Self Cite

303

273

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“…7 Patients with IRIS have increased plasma levels of inflammatory cytokines, 8,9 CD4 and CD8 cell activation, 8–10 increased CD4 cell production of pro-inflammatory cytokines in response to pathogen-derived antigens. 9–11 Patients with IRIS characteristically have inflammatory infiltrates of affected organs.…”

Section: Introductionmentioning

confidence: 99%

Effect of the CCR5 antagonist maraviroc on the occurrence of immune reconstitution inflammatory syndrome in HIV (CADIRIS): a double-blind, randomised, placebo-controlled trial

et al. 2014

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Background Immune Reconstitution Inflammatory Syndrome (IRIS) is a common complication of antiretroviral therapy (ART) in HIV-infected patients. IRIS is associated with an increased risk of hospitalization and death. We ascertained whether CCR5 blockade using maraviroc reduces the risk of IRIS. Methods The CADIRIS study was a randomized, double-blind, placebo-controlled, clinical trial that accrued subjects from five clinical sites in Mexico and one in South Africa between November 2009 and January 2012, and followed them for one year. The primary outcome was occurrence of IRIS by 24 weeks. HIV-infected adults, naïve to ART, with CD4 cells <100/μL, and HIVRNA >1,000 copies/mL were eligible. We screened 362 subjects; 279 met inclusion criteria, 3 refused participation, and 276 were randomized. Participants received maraviroc 600 mg twice daily or placebo added to an ART regimen that included tenofovir, emtricitabine, and efavirenz for 48 weeks. Findings There were 276 patients randomized (140 received maraviroc and 136 placebo). There was no difference in the time to IRIS events between treatment arms (HR 1·08, 95% CI (0·66, 1·77), log-rank test p=0·743). In total, 64 (23%) patients had IRIS events, 33 (24%) in the maraviroc arm and 31 (23%) in the placebo arm (p=0·88). Interpretation Maraviroc had no significant effect on frequency, time or severity of IRIS events after ART initiation. Including a CCR5 inhibitor in an initial treatment regimen does not confer a meaningful protection from the occurrence of IRIS in persons with advanced HIV infection. Funding The trial was funded as investigator initiated research by Pfizer Inc, New York, NY, USA. Trial Registration ClinicalTrials.gov. ID: NCT00988780 (http://clinicaltrials.gov/ct2/show/NCT00988780)

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“…As reviewed by Hart et al[43], constitutive expression of KLF2 in naïve T-cells is extinguished after T-cell stimulation, and cytokines involved in effector differentiation repress re-expression of KLF2. Loss of KLF2 leads, in turn, to transcriptional down-regulation of sphingosine 1-phosphate receptor 1 and thus activated T-cells are retained in lymphoid sites[51]. Furthermore, once CD8+ T-cells are activated, elevated levels of KLF2 are required to maintain the memory cell phenotype[52].…”

Section: Discussionmentioning

confidence: 99%

HIV vasculopathy

Hale

Longenecker

Jiang

et al. 2015

Aids

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Objective To determine the relationships between Krüppel-like Factors (KLF) 2 and 4, immune-activation, and sub-clinical vascular disease in HIV-infected patients on antiretroviral therapy. Design Double blind, randomized, placebo-controlled trial Methods We studied 74 HIV-infected adults on antiretroviral therapy enrolled in a randomized clinical trial of statin therapy. KLF2 and KLF4 gene expression was measured by quantitative polymerase chain reaction from peripheral blood mononuclear cells (PBMCs) at baseline and after 24 weeks of 10mg daily rosuvastatin or placebo. At the same time points, T-cell and monocyte activation were assessed by flow cytometry and vascular health was assessed by cardiac computed tomography and carotid ultrasound. Results KLF4 expression was negatively correlated with duration of antiretroviral therapy (r=−0.351, p=0.004) and positively correlated with measures of immune activation: pro-inflammatory monocytes [CD14+CD16+ (r=0.343, p=0.003)], patrolling monocytes [CD14dimCD16+ (r=0.276, p=0.017] and activated CD8+ T-lymphocytes [CD8+DR+CD38+ (r=0.264, p=0.023)]. KLF2 expression was negatively correlated with subclinical atherosclerosis: mean-mean common carotid artery intima media thickness (CIMT) (r= −0.231, p=0.048), mean-max CIMT (r= −0.271, p=0.020) and coronary artery calcium score (r=−0.254, p=0.029). There were no statistically significant changes in KLF2/4 expression in PBMCs after 24 weeks of rosuvastatin. Conclusions Expression of KLF4 in PBMCs positively correlates with cellular markers of immune activation, while KLF2 expression negatively correlates with markers of subclinical atherosclerosis in this HIV-infected population on antiretroviral therapy. Additional studies are needed to determine if targeted interventions might alter KLF2/4 expression to reduce inflammation and vascular risk in humans.

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Impaired T-cell responses to sphingosine-1-phosphate in HIV-1 infected lymph nodes

Abstract: Key Points S1P1 activity in human T cells can be reliably measured by assessing downstream signaling events induced upon S1P1 ligation. S1P1 activity is impaired in T cells from HIV-1+ lymph nodes.

Cited by 32 publications

References 50 publications

Residual Immune Dysregulation Syndrome in Treated HIV infection

Residual Immune Dysregulation Syndrome in Treated HIV infection

Effect of the CCR5 antagonist maraviroc on the occurrence of immune reconstitution inflammatory syndrome in HIV (CADIRIS): a double-blind, randomised, placebo-controlled trial

HIV vasculopathy

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