Monocyte Activation and Cardiovascular Disease in HIV Infection

RESEARCH HIGHLIGHT

Monocyte activation and cardiovascular disease in HIV infection

Hua Liang1,3, Zhe Xie2,3 and Tao Shen2

Cellular and Molecular Immunology (2017) 14, 960–962; doi:10.1038/cmi.2017.109; published online 30 October 2017

ntiretroviral therapy (ART) has monocytes can be activated by replicat- monocyte subsets represent an activated Aincreased the lifespan of HIV- ing virus, microbial translocation, status of monocytes, accompanied by infected individuals, which is now pro-inflammatory cytokines, and activated abundant CD16 expression. After pri- approaching that of the general popula- platelets. Monocytes in human blood mary HIV infection, endothelial cells tion. However, cardiovascular disease belong to three subsets: classical mono- become dysfunctional and express higher (CVD), including myocardial infarction, cytes (CD14highCD16 − ), intermediate levels of adhesion molecules and chemo- stroke, heart failure, and arrhythmia, is monocytes (CD14highCD16+), and non- kines to attract monocytes to the lesion still a main cause of mortality in HIV- classical monocytes (CD14dimCD16+). site; the monocytes are then activated. positive population. The risk of CVD in Classical monocytes possess the potential Activated monocytes infiltrate into the people living with HIV is about 1.5–2- for phagocytosis. They differentiate into intima (facilitated by CX3CL1) and dif- fold higher than that in the general M1 macrophages under inflammatory or ferentiate into macrophages, which then population.1 Even in those successfully activation conditions and phagocytose phagocytose oxidized LDL (oxLDL) and treated with ART, the incidence of CVD native low-density lipoproteins (LDL) form cholesterol-rich foam cells that is still higher than that in uninfected to form foam cells. Intermediate mono- ultimately develop into fibrous plaques. individuals.2 Thus, in addition to the cytes are a pro-inflammatory subset, In addition, HIV infection impairs cho- traditional risk factors associated with which secrete large amounts of pro- lesterol efflux of monocytes and increases CVD, other factors (such as ART per se, inflammatory cytokines and express che- foam cell formation via the pro- inflammation, and immune activation mokine receptors associated with ather- atherogenic cytokine TNF-α and reduced caused by HIV infection) may be osclerosis (such as CCR2, CX3CR1, and expression of genes regulating cholesterol involved in CVD development. CCR5). These cells generate reactive metabolism (for example, cholesterol Chronic immune activation, particu- oxygen species (ROS) and are proangio- transporter ABCA1 (ATP-binding cas- larly of monocytes/macrophages, contri- genic. Non-classical monocytes, also sette transporter A1)7). Notably, inflix- butes to HIV pathogenesis, and disease called ‘patrolling’ monocytes, patrol vas- imab (a TNF-α antagonist) failed to progression. During HIV infection, cular surfaces, and migrate into athero- reduce the incidence of advanced heart sclerotic lesions. Subjects with acute failure in an ATTACH trial.8 1State Key Laboratory of Infectious Disease Pre- coronary syndrome harbor increased In addition to the above, monocytes vention and Control, National Center for AIDS/ numbers of non-classical and intermedi- can form monocyte-platelet aggregates STD Control and Prevention, China CDC, Colla- ate monocytes, which promote (MPAs) with activated platelets via bind- borative Innovation Center for Diagnosis and atherogenesis.3 These two subsets are ing of P-selectin glycoprotein ligand-1 Treatment of Infectious Diseases, Beijing, China and 2Department of Microbiology and Center of also expanded in HIV-positive indivi- (PSGL-1) on monocytes to P-selectin Infectious Diseases, School of Basic Medical duals, including those with primary or (CD62P) on platelets. Upon injury, plate- Sciences, Peking University, Beijing, China chronic HIV infection and those success- lets are recruited to the lesion, where they 3 These authors contributed equally to this work. fully treated with ART.4,5 Ahighnumber become activated. Activated platelets Correspondence: Professor Tao Shen, Depart- ment of Microbiology and Center of Infectious of non-classical and intermediate mono- recruit more platelets and eventually form Diseases, School of Basic Medical Sciences, cytes is associated with the occurrence a thrombus. At the same time, activated Peking University, #38 Xueyuan Rd., Haidian and progression of CVD events, inde- platelets secrete pro-inflammatory cyto- District, Beijing 100191, China. pendently of traditional risk factors and kines to activate endothelial cells and E-mail: [email protected] 3,5,6 Received: 29 August 2017; Accepted: ART. The reasons for this are com- enhancemonocyterecruitment,adhe- 18 September 2017 plicated and unclear. These two sion, and activation. Monocytes are Monocyte activation and CVD in HIV infection HLianget al.

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Figure 1 Effect of activated monocytes in the occurrence of atherosclerosis in HIV-infected individuals. Endothelial cells are activated by HIV or injury, and platelets are recruited and activated to form a thrombus. Activated endothelial cells and platelets express adhesion molecules and secrete chemokines, which recruit and activate monocytes. Monocytes activated by endothelial cells, platelets, and other factors transmigrate into the intima and differentiate into macrophages that engulf oxLDL and form foam cells. Activated monocytes interact with activated platelets to form MPA, which further stimulates thrombus formation and increases production of proteolytic enzymes, resulting in plaque destabilization and rupture. HIV, human immunodeficiency virus; ART, antiretroviral therapy; PF4, platelet factor 4; LDL, low-density lipoprotein; oxLDL, oxidized LDL; PSGL-1, P-selectin glycoprotein ligand-1; ROS, reactive oxygen species; MPA, monocyte-platelet aggregate. activated through cell to cell contact or by high concentration around thrombi, at The levels of sCD14 and sCD163, cytokines. In a vicious circle, activated which the monocyte-platelet interaction two soluble markers of monocyte monocytes increase PSGL-1, CD86, occurs.9,10 Platelets promote monocytes activation, are elevated in HIV-positive CCR2, and CD11b expression and MPA to release proteolytic enzymes, which individuals.4,12 sCD14 is a receptor for formation, thereby attracting more degrade the extracellular matrix and lipopolysaccharide (LPS) and a marker monocytes to the lesion. MPA formation destabilize plaques (Figure 1). of microbial translocation. sCD14 is also is accompanied by monocyte activation Formation of MPAs and the interac- associated with coronary stenosis, cor- and platelet activation, along with tion between monocytes and platelets are onary artery calcium, and progression of increased cytokine and chemokine pro- highly correlated with CVD events.11 subclinical atherosclerosis in HIV- duction and adhesion molecules expres- Studies show that MPA levels are elevated infected individuals.12–14 sCD163 is a sion. Platelet-derived chemokines (such in those with ischemic heart failure, as scavenger receptor derived from ecto- as CXCL4, CCL5, and MIF) promote well as in those with primary and chronic domain shedding of membrane CD163. adhesion of monocytes to endothelial HIV infection, regardless of ART.4,11 sCD163 is recognized as a marker for cells. Tumor growth factor β (TGF-β) MPA levels in the three monocyte subsets atherosclerosis in HIV-negative popula- produced by activated platelets increases show a positive correlation with sCD163 tions and is associated with coronary CD16 expression and triggers classical levels in HIV-infected individuals, indi- artery calcium, mixed plaques, coronary monocytes to differentiate into inter- cating an association between increased stenosis, calcified plaques, and non- mediate or non-classical monocytes, pos- formation of MPA and monocyte activa- calcified coronary plaques in HIV- sibly through the p38 MAPK pathway. tion status.4 These studies indicate that positive individuals.12,15 Furthermore, Furthermore, platelet-derived chemokine the interaction between monocytes and there is a dose-dependent relationship platelet factor 4 (PF4) and CXCL12 can platelets plays a key role in CVD events, between sCD163 levels and the coronary modulate monocyte survival, monocyte and that MPA is a sensitive and appro- artery calcium score.9 differentiation into macrophages, and priate marker for monitoring monocyte Taken together, current researches foam cell formation. PF4 is present at and platelet activation. reveal that increased numbers of non-

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