Multifunctional T cells are the potential correlates of protection against HIV. Most cytokine-expressing cells were positive for only a single cytokine Figures 6 a and 6 b. There was a drop in single-positive cells concurrent with decreased frequencies of multifunctional cells, suggesting that the function of T cells is destroyed. These data suggest that, in addition to activating T cells, LPS influences their functional phenotypes.
These findings suggest that changes in T cell function during LPS stimulation become important factors for immune activation and viral replication inhibition. To identify hematological changes that are associated with LPS treatment, we examined longitudinal hematology data during LPS treatment. Most hematological parameters remained unchanged during LPS treatment data not show , while the number of leukocytes, monocytes, and neutrophils increased rapidly at day 1 in response to LPS treatment Figures 7 a , 7 b , and 7 c. Levels of leukocytes a were increased in LPS-treated Ch-RMs with concomitant increases in monocytes b and neutrophils c.
Platelet counts d were decreased after LPS stimulation. The percentages of monocytes e and neutrophils f were increased in blood. The leukocytes are the first line of immune defense against infection and respond rapidly to LPS. Elevated levels of leukocytes can be the result of inflammatory response and immune activation. A temporary drop in the circulating platelet counts were observed at day 1 after LPS treatment. We speculate that the decrease of platelet counts may be caused by increased activation and subsequent sequestration of platelets in platelet-monocyte aggregates as reported by Metcalf Pate et al.
Persistent immune activation is a hallmark of progressive HIV infection. The level of immune activation is more closely associated with disease progression compared to plasma VL [ 31 ]. Plasma levels of LPS are closely associated with the intestinal permeability degree. Accumulative evidence indicates that microbial translocation MT promotes systemic immune activation in chronic HIV infection [ 1 ]. As previously reported, the translocation of LPS contributes to the systemic immune activation in HIV-1 infection [ 33 ], and microbial translocation especially LPS has been associated with HIV disease progression [ 34 , 35 ].
LPS treatment induced a rapid, transient increase in activated T cells. In our study, increased levels of LPS were associated with increased T cell activation and proliferation and increased production of HIV in LPS-treated animals, suggesting that LPS administration directly causes viral associated immune activation. The levels of B cells were downregulated after LPS administration in SHIV-infected monkeys in our study, and a few days later the cell number increased again, which is consistent with a previous report showing that LPS and HIV synergistically induce memory B cell apoptosis [ 36 ].
These results are consistent with the findings of Catalfamo et al. They have the potential to rapidly produce cytokines and eliminate infected cells [ 38 ]. PD-1 expression is associated with cytokine production as well as T cell expansion [ 44 ]. The cytokine-releasing capacity is also an important function of T cells against HIV infection.
In HIV-infected individuals, the presence of polyfunctional T cells has been associated with superior control of viral infection [ 46 , 47 ]. We showed here that the upregulation of PD-1 in T cells after LPS administration is associated with alterations in the distribution of T cell subpopulations and with impaired expression of cytokines. We reconfirmed the findings that PD-1 can be used as a marker for aberrant distribution of T cell subpopulations in HIV-1 infection [ 48 ]. A potential limitation of the present study is the smaller animal size. However, it is important to consider that the experiment was performed in a controlled system.
In summary, our data provided a direct relationship between LPS and immune activation. LPS can directly stimulate immune activation, making more target cells available for viral exploitation. Increased viral replication in target cells may in turn exacerbate these changes and result in an altered T cell homeostasis during chronic HIV infection. Muhammad Shahzad from Department of Pharmacology at University of Health Sciences, Lahore, for review of the paper, suggestions, and comments.
The funding agencies had no role in study design, data collection and analysis, decision to publish, or preparation of the paper. National Center for Biotechnology Information , U. Journal List J Immunol Res v. J Immunol Res. Published online Dec 2.
Author information Article notes Copyright and License information Disclaimer. Received Aug 10; Accepted Nov 5. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Immune activation plays a significant role in the disease progression of HIV. Introduction Chronic immune activation and inflammatory cytokine production are the hallmarks of HIV infection [ 1 , 2 ]. Materials and Methods 2. Absolute Quantification of Major Leukocyte Subpopulations Direct cell surface staining for whole blood and absolute number analysis were performed according to standard procedures and appropriate concentrations in this study.
Results 3. Open in a separate window. Figure 1. Figure 2. Figure 3. Figure 4. Figure 5. Figure 6. Figure 7. Discussion Persistent immune activation is a hallmark of progressive HIV infection. Disclaimer The funding agencies had no role in study design, data collection and analysis, decision to publish, or preparation of the paper.
Conflict of Interests The authors declare that they have no conflict of interests. References 1. Brenchley J.
Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Biancotto A. Abnormal activation and cytokine spectra in lymph nodes of people chronically infected with HIV Rajasuriar R. Persistent immune activation in chronic HIV infection: do any interventions work? Mehandru S. Hayes T. Gordon S. Journal of Immunology. Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nature Medicine. Mavigner M. Mucosal Immunology. Guglani L. Th17 cytokines in mucosal immunity and inflammation.
Sugimoto K. IL ameliorates intestinal inflammation in a mouse model of ulcerative colitis. Park H. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin Nature Immunology. Differential Th17 CD4 T-cell depletion in pathogenic and nonpathogenic lentiviral infections. Paiardini M. Th17 cells in natural SIV hosts. Microbial translocation across the GI tract. Annual Review of Immunology. Prasad S. Inflammatory processes have differential effects on claudins 2, 3 and 4 in colonic epithelial cells.
Laboratory Investigation. Chiba H. Science Signaling. Smith A. A role for syndecan-1 and claudin-2 in microbial translocation during HIV-1 infection. Journal of Acquired Immune Deficiency Syndromes. Ruemmele F. Suy A. Hayashi F. The innate immune response to bacterial flagellin is mediated by toll-like receptor 5. Shan L. Unraveling the relationship between microbial translocation and systemic immune activation in HIV infection.
Compromised gastrointestinal integrity in pigtail macaques is associated with increased microbial translocation, immune activation, and IL production in the absence of SIV infection. Neaton J.
HIV as a Cause of Immune Activation and Immunosenescence
Soluble biomarkers and morbidity and mortality among people infected with HIV: summary of published reports from to Nakanjako D. High T-cell immune activation and immune exhaustion among individuals with suboptimal CD4 recovery after 4 years of antiretroviral therapy in an African cohort. BMC Infectious Diseases. Fernandez S. Immune activation and the pathogenesis of HIV disease: implications for therapy.
Journal of HIV Therapy. Ostrowski S. Immune activation in chronic HIV infection. Danish Medical Bulletin. Funderburg N. Increased tissue factor expression on circulating monocytes in chronic HIV infection: relationship to in vivo coagulation and immune activation. Clinical Microbiology Reviews.
Bukh A. Endotoxemia is associated with altered innate and adaptive immune responses in untreated HIV-1 infected individuals. Muller-Trutwin M. Role for plasmacytoid dendritic cells in anti-HIV innate immunity. Immunology and Cell Biology. Grossman Z.
Duggal S. HIV and malnutrition: effects on immune system. Cohen Stuart J. Bucy R. Wolf K. Antiretroviral therapy reduces markers of endothelial and coagulation activation in patients infected with human immunodeficiency virus type 1. Malherbe G. Mediators of Inflammation. Estes J.
Microbial endocrinology: host–bacteria communication within the gut microbiome
Collagen deposition limits immune reconstitution in the gut. Zeng M. Asmuth D. Role of intestinal myofibroblasts in HIV-associated intestinal collagen deposition and immune reconstitution following combination antiretroviral therapy. Lederman M. Residual immune dysregulation syndrome in treated HIV infection.
Advances in Immunology. Reeves R. Favre D. Tryptophan catabolism by indoleamine 2,3-dioxygenase 1 alters the balance of TH17 to regulatory T cells in HIV disease. Science Translational Medicine. Khoury G. The role of naive T-cells in HIV-1 pathogenesis: an emerging key player.
Clinical Immunology. The thymus during HIV disease: role in pathogenesis and in immune recovery. Current HIV Research. Evidence of premature immune aging in patients thymectomized during early childhood. Manjati T. Immune activation is associated with decreased thymic function in asymptomatic, untreated HIV-infected individuals. Ho Tsong Fang R. The role of the thymus in HIV infection: a 10 year perspective. Kolte L. Association between larger thymic size and higher thymic output in human immunodeficiency virus-infected patients receiving highly active antiretroviral therapy.
Vigano A. Thymus volume correlates with the progression of vertical HIV infection. Hakim F. Age-dependent incidence, time course, and consequences of thymic renewal in adults. Howcroft T. The role of inflammation in age-related disease. Kam L. Cytokine-based therapies in inflammatory bowel disease. Current Opinion in Gastroenterology.
Olsson J. Boulware D. Kaplan R. T cell activation and senescence predict subclinical carotid artery disease in HIV-infected women. Macias J. Calza L.
- Microbial translocation across the GI tract. - Semantic Scholar.
- O Dia Filipe Comeu Tudo (Portuguese Edition).
- That Sushi Place!
Immunological Reviews. Karpatkin S. Platelet and coagulation defects associated with HIVinfection. Journal of Thrombosis and Haemostasis. Jacobson M. Thrombotic complications in patients infected with HIV in the era of highly active antiretroviral therapy: a case series. Periard D. Atherogenic dyslipidemia in HIV-infected individuals treated with protease inhibitors. The Swiss HIV cohort study. Koppel K. Hypofibrinolytic state in HIVinfected patients treated with protease inhibitor-containing highly active antiretroviral therapy. Dressman J. HIV protease inhibitors promote atherosclerotic lesion formation independent of dyslipidemia by increasing CDdependent cholesteryl ester accumulation in macrophages.
Foam cells in atherosclerosis. Clinica Chimica Acta. Zidar D. Galkina E. Immune and inflammatory mechanisms of atherosclerosis. Freiberg M. HIV infection and the risk of acute myocardial infarction. Butt A. Risk of heart failure with human immunodeficiency virus in the absence of prior diagnosis of coronary heart disease.
Archives of Internal Medicine. Sico J. HIV status and the risk of ischemic stroke among men. Tseng Z. Sudden cardiac death in patients with human immunodeficiency virus infection. Journal of the American College of Cardiology. Childs B. Senescent intimal foam cells are deleterious at all stages of atherosclerosis. Islam F.
Relative risk of renal disease among people living with HIV: a systematic review and meta-analysis. BMC Public Health. Meir-Shafrir K. Accelerated aging in HIV patients. Rambam Maimonides Medical Journal. Medapalli R. HIV-associated nephropathy: pathogenesis. Current Opinion in Nephrology and Hypertension. Rifkin D. Does inflammation fuel the fire in CKD? American Journal of Kidney Disease.
Becker G. The role of tubulointerstitial injury in chronic renal failure. Remuzzi G. Understanding the nature of renal disease progression. Kidney International. Cytokine cross-talk between tubular epithelial cells and interstitial immunocompetent cells. Chen P. Segerer S. Chemokines, chemokine receptors, and renal disease: from basic science to pathophysiologic and therapeutic studies. Journal of the American Society of Nephrology.
Canaud G. The kidney as a reservoir for HIV-1 after renal transplantation. Parkhie S. Characteristics of patients with HIV and biopsy-proven acute interstitial nephritis. Clinical Journal of the American Society of Nephrology. Ivey N. Acquired immunodeficiency syndrome and the blood-brain barrier. Journal of Neurovirology. Highleyman L. Inflammation, immune activation, and HIV. Valdez A. Untangling the Gordian knot of HIV, stress, and cognitive impairment.
HIV as a Cause of Immune Activation and Immunosenescence
Neurobiology of Stress. Bora A. Burdo T. Abstract Sartori A. The impact of inflammation on cognitive function in older adults: implications for healthcare practice and research. Journal of Neuroscience Nursing. Chen N. Fate of microglia during HIV-1 infection: from activation to senescence? Garvey L. Tyor W. Cytokine expression in the brain during the acquired immunodeficiency syndrome. Annals of Neurology. Stanley L. Journal of Neuropathology and Experimental Neurology. Flanary B. Progressive telomere shortening occurs in cultured rat microglia, but not astrocytes. Caldeira C. Microglia change from a reactive to an age-like phenotype with the time in culture.
Frontiers of Cellular Neuroscience. Spittau B. Aging microglia—phenotypes, functions and implications for age-related neurodegenerative diseases. Frontiers in Aging Neuroscience. Triant V. Journal of Clinical Endocrinology and Metabolism. Fakruddin J. The Journal of Biological Chemistry. Stellbrink H. Comparison of changes in bone density and turnover with abacavir-lamivudine versus tenofovir-emtricitabine in HIV-infected adults: week results from the ASSERT study.
Ginaldi L. Osteoporosis, inflammation and ageing. Immunity and Ageing. Crum-Cianflone N. Animals and infection. At the time of virus infection, therapy with sevelamer carbonate Renvela 2, mg, 3 times per day was initiated in 4 PTMs and was administered for 3 months. Remaining PTMs were used as untreated controls. During the follow-up, one of the PTMs in the study group died at day 53 after infection, due to causes unrelated to SIV infection or treatment. Sample collection. Blood was collected from all PTMs prior to infection, biweekly for 2 weeks, weekly for 4 weeks, and bimonthly thereafter.
Intestinal biopsies were collected prior to infection, during acute infection, at the set point, and during chronic infection, as described previously 11 , 28 , Samples were processed as described previously 11 , 28 , Laboratory assessment. Whole blood and mononuclear cells isolated from intestinal biopsies were analyzed by flow cytometry, as described previously 9. Plasma levels of LPS and sCD14 were measured as described previously 9 , 11 , to assess the levels of microbial translocation. Results were further confirmed by immunohistochemical staining for LPS, which was performed as described previously 18 on formalin-fixed, paraffin-embedded LNs collected prior to infection and at 2 time points during chronic infection Cytokine and chemokine testing and D-dimer testing were performed as previously described 9.
Differences in late temporal dynamics were analyzed using mixed-effects models, with each macaque as the grouping factor to account for the repeated measurements made in that animal. Models with fixed effects for time and treatment, with or without interactions, were tested. When an interaction was significant, we describe this difference in the text. Assumption on the distribution of residuals and appropriateness of the fitted values were checked by visual inspection of residual and fitted plots.
The best model for the data was chosen by comparing the log likelihood. All P values of less than 0. Study approval. We thank Jason Brenchley and Jake Estes for helpful discussion. Pandrea , R01 RR to C. Apetrei and I. Pandrea , 5P01 AI to A. Landay , and P30 AI to A. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. See the related article at Unraveling the relationship between microbial translocation and systemic immune activation in HIV infection.
Go to JCI Insight. Unraveling the relationship between microbial translocation and systemic immune activation in HIV infection. Liang Shan, Robert F. Siliciano Liang Shan, Robert F. Category: Commentary.
Related Microbial Translocation Across the GI Tract (Annual Review of Immunology Book 30)
Copyright 2019 - All Right Reserved