Soluble CD163 Made by Monocyte/Macrophages Is a Novel Marker of HIV Activity in Early and Chronic Infection Prior to and After Antiretroviral Therapy

Department of Biology, Boston College, Chestnut Hill, MA, USA.
The Journal of Infectious Diseases (Impact Factor: 6). 07/2011; 204(1):154-63. DOI: 10.1093/infdis/jir214
Source: PubMed


CD163, a monocyte- and macrophage-specific scavenger receptor, is shed during activation as soluble CD163 (sCD163). We have previously demonstrated that monocyte expansion from bone marrow with simian immunodeficiency virus (SIV) infection correlated with plasma sCD163, the rate of AIDS progression, and the severity of macrophage-mediated pathogenesis. Here, we examined sCD163 in human immunodeficiency virus (HIV) infection. sCD163 was elevated in the plasma of individuals with chronic HIV infection (>1 year in duration), compared with HIV-seronegative individuals. With effective antiretroviral therapy (ART), sCD163 levels decreased in parallel with HIV RNA levels but did not return to HIV-seronegative levels, suggesting the presence of residual monocyte/macrophage activation even with plasma viral loads below the limit of detection. In individuals with early HIV infection (≤1 year in duration), effective ART resulted in decreased sCD163 levels that were comparable to levels in HIV-seronegative individuals. sCD163 levels in plasma were positively correlated with the percentage of CD14+CD16+ monocytes and activated CD8+HLA-DR+CD38+ T lymphocytes and were inversely correlated with CD163 expression on CD14+CD16+ monocytes. With ART interruption in subjects with early HIV infection, sCD163 and plasma virus levels spiked but rapidly returned to baseline with reinitiation of ART. This study points to the utility of monocyte- and macrophage-derived sCD163 as a marker of HIV activity that links viral replication with monocyte and macrophage activation. These observations underscore the significance of monocyte and macrophage immune responses with HIV pathogenesis.

Download full-text


Available from: Tricia H Burdo
  • Source
    • "We also found that sCD14, RANTES, and MCP-1 were correlated to the percent of CD14+ CD16+ monocytes out of total blood monocytes. CD14+ CD16+ monocytes are an activated population of monocytes that highly express CCR2, the receptor for MCP-1, and CD163[58,59]. Elevated levels of RANTES and MCP-1 in plasma were associated with moderate or Fig. 5RANTES, MCP-1, and sCD137 protein levels in DRG tissue. RANTES (a), MCP-1 (b), and sCD137 (c) were detected by Luminex multiplex assay in DRG tissue lysate. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background: Peripheral neuropathy (PN) continues to be a major complication of human immunodeficiency virus (HIV) infection despite successful anti-retroviral therapy. Human HIV-PN can be recapitulated in a CD8-depleted, simian immunodeficiency virus (SIV)-infected rhesus macaque animal model, characterized by a loss of intraepidermal nerve fiber density (IENFD) and damage to the dorsal root ganglia (DRG). Increased monocyte traffic to the DRG has previously been associated with severe DRG pathology, as well as a loss in IENFD. Here, we sought to characterize the molecular signals associated with monocyte activation and trafficking to the DRGs. Methods: Eleven SIV-infected CD8-depleted rhesus macaques were compared to four uninfected control animals. sCD14, sCD163, sCD137, regulated on activation normal T cell expressed and secreted (RANTES), and monocyte chemoattractant protein 1 (MCP-1) were measured in plasma and the latter three proteins were also quantified in DRG tissue lysates. All SIV-infected animals received serial skin biopsies to measure IENFD loss as well as BrdU inoculations to measure monocyte turnover during the course of infection. The number of BrdU+ and CD14+ CD16+ peripheral blood monocytes was determined by flow cytometry. The number of MAC387+, CCR2+, CCR5+, and CD137+ cells in DRG tissue was quantified by immunohistochemistry. Results: sCD14, sCD163, MCP-1, and sCD137 increased significantly in plasma from pre-infection to necropsy. Plasma sCD163 and RANTES inversely correlated with IENFD. Additionally, sCD137 in DRG tissue lysate was elevated with severe DRG pathology and associated with the recruitment of MAC387+ cells to DRG. Elevated numbers of CCR5+ and CCR2+ satellite cells in the DRG were found, suggesting a chemotactic role of their ligands, RANTES, and MCP-1 in recruiting monocytes to the tissue. Conclusions: We characterized the role of systemic (plasma) and tissue-specific (DRG) monocyte activation and associated cytokines in the pathogenesis of SIV-PN. We identified sCD163 and RANTES as potential biomarkers for HIV-PN, as these were associated with a loss of IENFD. Additionally, we identified CD137 signaling to play a role in MAC387+ cell traffic to DRG and possibly contribute to severe pathology. These studies highlight the role of monocyte activation and traffic in the pathogenesis of SIV-PN, while identifying specific signaling proteins for future pharmacological blockade.
    Full-text · Article · Dec 2015 · Journal of Neuroinflammation
  • Source
    • "Both CSF and plasma expression of sCD163 and sCD14 correlated within compartments (Fig. 2a, b), as did CSF NFL and pNFH (data not shown). The only other similar intracompartment correlations of monocyte activation markers we are aware of in the HIV literature have demonstrated a correlation between plasma sCD163 and CSF neopterin (Burdo et al. 2013) and plasma sCD163 and plasma sCD14 (Burdo et al. 2011). The strength and significance of the correlation shown in Fig. 2 suggests that both sCD163 and sCD14 similarly reflect monocyte activation in the CSF (and either may be used with confidence as a CSF marker of monocyte activation) and supports the conclusion that these markers are predictably detecting monocyte/ macrophage activation and neuronal injury in these subjects. "
    [Show abstract] [Hide abstract]
    ABSTRACT: HIV-associated neurocognitive disorders (HAND) affect up to 50 % of HIV-infected adults, independently predict HIV morbidity/mortality, and are associated with neuronal damage and monocyte activation. Cerebrospinal fluid (CSF) neurofilament subunits (NFL, pNFH) are sensitive surrogate markers of neuronal damage in several neurodegenerative diseases. In HIV, CSF NFL is elevated in individuals with and without cognitive impairment, suggesting early/persistent neuronal injury during HIV infection. Although individuals with severe cognitive impairment (HIV-associated dementia (HAD)) express higher CSF NFL levels than cognitively normal HIV-infected individuals, the relationships between severity of cognitive impairment, monocyte activation, neurofilament expression, and systemic infection are unclear. We performed a retrospective cross-sectional study of 48 HIV-infected adults with varying levels of cognitive impairment, not receiving antiretroviral therapy (ART), enrolled in the CNS Anti-Retroviral Therapy Effects Research (CHARTER) study. We quantified NFL, pNFH, and monocyte activation markers (sCD14/sCD163) in paired CSF/plasma samples. By examining subjects off ART, these correlations are not confounded by possible effects of ART on inflammation and neurodegeneration. We found that CSF NFL levels were elevated in individuals with HAD compared to cognitively normal or mildly impaired individuals with CD4+ T-lymphocyte nadirs ≤200. In addition, CSF NFL levels were significantly positively correlated to plasma HIV-1 RNA viral load and negatively correlated to plasma CD4+ T-lymphocyte count, suggesting a link between neuronal injury and systemic HIV infection. Finally, CSF NFL was significantly positively correlated with CSF pNFH, sCD163, and sCD14, demonstrating that monocyte activation within the CNS compartment is directly associated with neuronal injury at all stages of HAND.
    Full-text · Article · Mar 2015 · Journal of NeuroVirology
  • Source
    • "Plasma sCD163 is also increased during acute HIV infection compared to HIV-seronegative controls though at lower levels than chronic infection [89]. In acutely infected patients treated with cART for three months, sCD163 levels are similar to those in HIV-seronegative controls [89], suggesting that early cART initiation can limit mononuclear phagocyte activation. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Combined antiretroviral therapy (cART) extends the lifespan and the quality of life for HIV-infected persons but does not completely eliminate chronic immune activation and inflammation. The low level of chronic immune activation persisting during cART-treated HIV infection is associated with the development of diseases which usually occur in the elderly. Although T-cell activation has been extensively examined in the context of cART-treated HIV infection, monocyte activation is only beginning to be recognized as an important source of inflammation in this context. Here we examine markers and sources of monocyte activation during cART-treated HIV infection and discuss the role of monocytes during cardiovascular disease, HIV-associated neurocognitive disorder, and innate immune aging.
    Full-text · Article · Jun 2014 · Research Journal of Immunology
Show more