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Monocyte activation and cardiovascular disease in HIV infection

Cellular & Molecular Immunology volume 14, pages 960–962 (2017)Cite this article

Antiretroviral therapy (ART) has increased the lifespan of HIV-infected individuals, which is now approaching that of the general population. However, cardiovascular disease (CVD), including myocardial infarction, stroke, heart failure, and arrhythmia, is still a main cause of mortality in HIV-positive population. The risk of CVD in people living with HIV is about 1.5–2-fold higher than that in the general population.1 Even in those successfully treated with ART, the incidence of CVD is still higher than that in uninfected individuals.2 Thus, in addition to the traditional risk factors associated with CVD, other factors (such as ART per se, inflammation, and immune activation caused by HIV infection) may be involved in CVD development.

Chronic immune activation, particularly of monocytes/macrophages, contributes to HIV pathogenesis, and disease progression. During HIV infection, monocytes can be activated by replicating virus, microbial translocation, pro-inflammatory cytokines, and activated platelets. Monocytes in human blood belong to three subsets: classical monocytes (CD14highCD16−), intermediate monocytes (CD14highCD16+), and non-classical monocytes (CD14dimCD16+). Classical monocytes possess the potential for phagocytosis. They differentiate into M1 macrophages under inflammatory or activation conditions and phagocytose native low-density lipoproteins (LDL) to form foam cells. Intermediate monocytes are a pro-inflammatory subset, which secrete large amounts of pro-inflammatory cytokines and express chemokine receptors associated with atherosclerosis (such as CCR2, CX3CR1, and CCR5). These cells generate reactive oxygen species (ROS) and are proangiogenic. Non-classical monocytes, also called ‘patrolling’ monocytes, patrol vascular surfaces, and migrate into atherosclerotic lesions. Subjects with acute coronary syndrome harbor increased numbers of non-classical and intermediate monocytes, which promote atherogenesis.3 These two subsets are also expanded in HIV-positive individuals, including those with primary or chronic HIV infection and those successfully treated with ART.4, 5 A high number of non-classical and intermediate monocytes is associated with the occurrence and progression of CVD events, independently of traditional risk factors and ART.3, 5, 6 The reasons for this are complicated and unclear. These two monocyte subsets represent an activated status of monocytes, accompanied by abundant CD16 expression. After primary HIV infection, endothelial cells become dysfunctional and express higher levels of adhesion molecules and chemokines to attract monocytes to the lesion site; the monocytes are then activated. Activated monocytes infiltrate into the intima (facilitated by CX3CL1) and differentiate into macrophages, which then phagocytose oxidized LDL (oxLDL) and form cholesterol-rich foam cells that ultimately develop into fibrous plaques. In addition, HIV infection impairs cholesterol efflux of monocytes and increases foam cell formation via the pro-atherogenic cytokine TNF-α and reduced expression of genes regulating cholesterol metabolism (for example, cholesterol transporter ABCA1 (ATP-binding cassette transporter A1)7). Notably, infliximab (a TNF-α antagonist) failed to reduce the incidence of advanced heart failure in an ATTACH trial.8

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References

  1. Islam FM, Wu J, Jansson J, Wilson DP . Relative risk of cardiovascular disease among people living with HIV: a systematic review and meta-analysis. HIV Med 2012; 13: 453–468.

    CAS  PubMed  Google Scholar 

  2. Hanna DB, Post WS, Deal JA, Hodis HN, Jacobson LP, Mack WJ et al. HIV infection is associated with progression of subclinical carotid atherosclerosis. Clin Infect Dis 2015; 61: 640–650.

    Article  CAS  Google Scholar 

  3. Chow DC, Kagihara JM, Zhang G, Souza SA, Hodis HN, Li Y et al. Non-classical monocytes predict progression of carotid artery bifurcation intima-media thickness in HIV-infected individuals on stable antiretroviral therapy. HIV Clin Trials 2016; 17: 114–122.

    Article  CAS  Google Scholar 

  4. Liang H, Duan Z, Li D, Wang Z, Ren L, Shen T et al. Higher levels of circulating monocyte-platelet aggregates are correlated with viremia and increased sCD163 levels in HIV-1 infection. Cell Mol Immunol 2015; 12: 435–443.

    Article  CAS  Google Scholar 

  5. Funderburg NT, Zidar DA, Shive C, Lioi A, Mudd J, Musselwhite LW et al. Shared monocyte subset phenotypes in HIV-1 infection and in uninfected subjects with acute coronary syndrome. Blood 2012; 120: 4599–4608.

    Article  CAS  Google Scholar 

  6. Baker JV, Hullsiek KH, Singh A, Wilson E, Henry K, Lichtenstein K et al. Immunologic predictors of coronary artery calcium progression in a contemporary HIV cohort. AIDS 2014; 28: 831–840.

    Article  CAS  Google Scholar 

  7. Maisa A, Hearps AC, Angelovich TA, Pereira CF, Zhou J, Shi MD et al. Monocytes from HIV-infected individuals show impaired cholesterol efflux and increased foam cell formation after transendothelial migration. AIDS 2015; 29: 1445–1457.

    Article  CAS  Google Scholar 

  8. Chung ES, Packer M, Lo KH, Fasanmade AA, Willerson JT . Randomized, double-blind, placebo-controlled, pilot trial of infliximab, a chimeric monoclonal antibody to tumor necrosis factor-alpha, in patients with moderate-to-severe heart failure: results of the anti-TNF Therapy Against Congestive Heart Failure (ATTACH) trial. Circulation 2003; 107: 3133–3140.

    Article  CAS  Google Scholar 

  9. Scheuerer B, Ernst M, Durrbaum-Landmann I, Fleischer J, Grage-Griebenow E, Brandt E et al. The CXC-chemokine platelet factor 4 promotes monocyte survival and induces monocyte differentiation into macrophages. Blood 2000; 95: 1158–1166.

    CAS  PubMed  Google Scholar 

  10. Chatterjee M, von Ungern-Sternberg SN, Seizer P, Schlegel F, Buttcher M, Sindhu NA et al. Platelet-derived CXCL12 regulates monocyte function, survival, differentiation into macrophages and foam cells through differential involvement of CXCR4-CXCR7. Cell Death Dis 2015; 6: e1989.

    Article  CAS  Google Scholar 

  11. Wrigley BJ, Shantsila E, Tapp LD, Lip GY . Increased formation of monocyte-platelet aggregates in ischemic heart failure. Circ Heart Fail 2013; 6: 127–135.

    Article  CAS  Google Scholar 

  12. Ahmed M, Mustfa N . Hot tub Legionella pneumonia outbreak. Eur Respir J 2014; 44: 1379–1381.

    Article  Google Scholar 

  13. Longenecker CT, Jiang Y, Orringer CE, Gilkeson RC, Debanne S, Funderburg NT et al. Soluble CD14 is independently associated with coronary calcification and extent of subclinical vascular disease in treated HIV infection. AIDS 2014; 28: 969–977.

    Article  CAS  Google Scholar 

  14. Kelesidis T, Kendall MA, Yang OO, Hodis HN, Currier JS . Biomarkers of microbial translocation and macrophage activation: association with progression of subclinical atherosclerosis in HIV-1 infection. J Infect Dis 2012; 206: 1558–1567.

    Article  CAS  Google Scholar 

  15. Fitch KV, Srinivasa S, Abbara S, Burdo TH, Williams KC, Eneh P et al. Noncalcified coronary atherosclerotic plaque and immune activation in HIV-infected women. J Infect Dis 2013; 208: 1737–1746.

    Article  Google Scholar 

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Acknowledgements

This work was financially supported by the State Key Laboratory of Infectious Disease Prevention and Control (2015SKLID506) and the National Science and Technology Major Project of China (2017ZX10202101-003, 2017ZX10301101-001, and 2017ZX09309008-003).

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  1. Hua Liang and Zhe Xie: These authors contributed equally to this work.

Authors and Affiliations

  1. State Key Laboratory of Infectious Disease Prevention and Control, National Center for AIDS/STD Control and Prevention, China CDC, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Beijing, China

    Hua Liang

  2. Department of Microbiology and Center of Infectious Diseases, School of Basic Medical Sciences, Peking University, Beijing, China

    Zhe Xie & Tao Shen

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  1. Hua Liang
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Correspondence to Tao Shen.

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Liang, H., Xie, Z. & Shen, T. Monocyte activation and cardiovascular disease in HIV infection. Cell Mol Immunol 14, 960–962 (2017). https://doi.org/10.1038/cmi.2017.109

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