Macrophages Accumulate in the Gut Mucosa of Untreated HIV-infected Patients

Allers, Kristina; Fehr, Mira; Conrad, Kristina; Epple, Hans Jörg; Schürmann, Dirk; Geelhaar‐Karsch, Anika; Schinnerling, Katina; Moos, Verena; Schneider, Thomas

doi:10.1093/infdis/jit547

Cited by 72 publications

(90 citation statements)

References 47 publications

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“…Our data join an increasing body of evidence suggesting that high viral load and low CD4 count may be associated with changes in monocyte functional responses, including greater monocyte turnover (associated with plasma sCD163) (40,41), tissue migration (40,41,76), and macrophage apoptosis in tissue (41). This study complements studies with SIV-infected macaques (using in vivo bromodeoxyuridine [BrdU] labeling) in which disease progression (i.e., high viral load) was associated with increased monocyte turnover, which may be associated with higher levels of apoptosis (40,41).…”

Section: Cd16supporting

confidence: 78%

Shift in Monocyte Apoptosis with Increasing Viral Load and Change in Apoptosis-Related ISG/Bcl2 Family Gene Expression in Chronically HIV-1-Infected Subjects

Patro

Pal

et al. 2015

J Virol

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Although monocytes and macrophages are targets of HIV-1-mediated immunopathology, the impact of high viremia on activation-induced monocyte apoptosis relative to monocyte and macrophage activation changes remains undetermined. In this study, we determined constitutive and oxidative stress-induced monocyte apoptosis in uninfected and HIV ؉ individuals across a spectrum of viral loads (n ‫؍‬ 35; range, 2,243 to 1,355,998 HIV-1 RNA copies/ml) and CD4 counts (range, 26 to 801 cells/mm 3 ). Both constitutive apoptosis and oxidative stress-induced apoptosis were positively associated with viral load and negatively associated with CD4, with an elevation in apoptosis occurring in patients with more than 40,000 (4.6 log) copies/ml. As expected, expression of Rb1 and interferon-stimulated genes (ISGs), plasma soluble CD163 (sCD163) IMPORTANCEThis study characterized differential monocyte activation, apoptosis, and apoptosis-related gene expression in low-versus highlevel viremic HIV-1 patients, suggesting a shift in apoptosis regulation that may be associated with disease state. Using single and multivariable analysis of monocyte activation parameters and gene expression, we supported the hypothesis that monocyte apoptosis in HIV disease is a reflection of viremia and activation state with contributions from gene expression changes within the ISG and Bcl2 gene families. Understanding monocyte apoptosis response may inform HIV immunopathogenesis, retention of infected macrophages, and monocyte turnover in low-or high-viral-load states.

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Section: Cd16supporting

confidence: 78%

Shift in Monocyte Apoptosis with Increasing Viral Load and Change in Apoptosis-Related ISG/Bcl2 Family Gene Expression in Chronically HIV-1-Infected Subjects

Patro

Pal

et al. 2015

J Virol

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“…Likewise, Allers et al (6) found that macrophages were significantly enriched in the gut of untreated HIV patients. This was accompanied by a corresponding decrease in blood monocytes and increased expression of gut homing receptor ␤7 on these cells, suggesting that mucosal homing blood monocytes may be a major source of macrophages that infiltrate the gut mucosa.…”

Section: The Gut Macrophage Reservoir In Hiv Infectionmentioning

confidence: 95%

“…Morphologically, gut macrophages are similar to most resident tissue macrophages, with a mononuclear shape and a granular cytoplasm, and they are highly phagocytic and microbicidal (3)(4)(5). They express major histocompatibility complex (MHC) class II, CD36, CD68, CD163 (6,7), and CD209 (7) but have low levels of CD80, CD86, and CD40 (8)(9)(10)(11). Unlike monocytes in peripheral blood that are largely CD14 ϩ , human mucosal macrophages in the gut have been shown to express a CD13 ϩ CD14 Ϫ CD16 Ϫ CD64 Ϫ CD89 Ϫ CD32 Ϫ phenotype (12,13).…”

mentioning

confidence: 99%

Gastrointestinal Tract and the Mucosal Macrophage Reservoir in HIV Infection

Brown¹,

Mattapallil²

2014

Clin. Vaccine Immunol.

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The gastrointestinal tract (GIT) is a primary site for human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) infection, replication, and dissemination. After an initial explosive phase of infection, HIV establishes latency. In addition to CD4 T cells, macrophages are readily infected, which can persist for long periods of time. Though macrophages at various systemic sites are infected, those present in the GIT constitute a major cellular reservoir due to the abundance of these cells at mucosal sites. Here, we review some of the important findings regarding what is known about the macrophage reservoir in the gut and explore potential approaches being pursued in the field to reduce this reservoir. The development of strategies that can lead to a functional cure will need to incorporate approaches that can eradicate the macrophage reservoir in the GIT. Macrophages are one of the most abundant immune cells in the gut (1, 2). Morphologically, gut macrophages are similar to most resident tissue macrophages, with a mononuclear shape and a granular cytoplasm, and they are highly phagocytic and microbicidal (3-5). They express major histocompatibility complex (MHC) class II, CD36, CD68, CD163 (6, 7), and CD209 (7) but have low levels of CD80, CD86, and CD40 (8-11). Unlike monocytes in peripheral blood that are largely CD14 ϩ , human mucosal macrophages in the gut have been shown to express aϪ phenotype (12, 13). The expression of CD4 and CCR5/CXCR4 key receptors for human immunodeficiency virus (HIV) infection, on macrophage populations has been shown to differ based on the sites the cells reside in. Shen et al. (14) showed that vaginal macrophages expressed CD4 and CCR5/CXCR4 similarly to blood monocytes, whereas intestinal macrophages expressed little or no detectable CD4 and CCR5/CXCR4 (15-17).Interestingly, under normal conditions or in response to Tolllike receptor (TLR) ligands, gut macrophages constitutively secrete anti-inflammatory cytokines, such as interleukin-10 (IL-10), rather than proinflammatory mediators, such as IL-12, IL-23, tumor necrosis factor alpha (TNF-␣), IL-1, IL-6, and interferoninducible protein 10 (IP-10) (18)(19)(20)(21)(22), suggesting that intestinal macrophages may be critical for maintaining immune homeostasis in the gastrointestinal tract (6). Smythies et al. (23) reported that intestinal macrophages displayed significant inflammation anergy even though they had avid phagocytic and bactericidal activity. Depletion of mucosal macrophages was shown to be associated with increased susceptibility to colitis and graft-versus-host disease in mice (24-26). Likewise, altering the phenotype of macrophages to that of a proinflammatory phenotype as seen during HIV replication was associated with increased inflammation and tissue damage (27).In addition to their role in maintaining mucosal immune homeostasis, gut macrophages, like dendritic cells (DC), have been shown to sample microbes directly from the intestinal lumen and transfer these antigens to DC for processing or tran...

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“…Aberrations in immunological responses are not limited to a loss of CD4 ϩ T cells and extend to inappropriate lymphocyte priming, proliferation, and functional exhaustion and dysfunctional antigen presentation and cytokine secretion by dendritic cells (DCs) (7,8). Despite the welldocumented roles of macrophages in mitigating the translocation of microbial products and in orchestrating appropriate immune responses, a comprehensive understanding of the contributions of tissue-resident macrophages to HIV and SIV disease progression is lacking, with some studies suggesting functional abnormalities within myeloid cells of HIV-infected humans or SIV-infected macaques (9)(10)(11)(12)(13)(14)(15).…”

mentioning

confidence: 99%

Macrophages Are Phenotypically and Functionally Diverse across Tissues in Simian Immunodeficiency Virus-Infected and Uninfected Asian Macaques

Ortiz

DiNapoli

Brenchley

2015

J Virol

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Macrophages regulate tissue immunity, orchestrating the initiation and resolution of antimicrobial immune responses and repair of damaged tissue architecture. Their dysfunction can, thus, manifest in either pro-and anti-inflammatory responses. Indeed, despite the importance of macrophage function in health and disease, the role of tissue-resident macrophages in human immunodeficiency virus (HIV) disease progression remains incompletely defined. Here, we use flow cytometry to assess the phenotypes and functions of macrophages isolated from the spleens, axillary lymph nodes, colons, jejuna, and livers of healthy and chronically simian immunodeficiency virus (SIV)-infected Asian macaques, the prominent nonhuman primate model for HIV infection. Our data demonstrate that macrophages from healthy animals exhibit considerable phenotypic and functional heterogeneity across tissues and across a variety of stimuli. Further, our analysis reveals changes in the lipopolysaccharide (LPS) responsiveness of macrophages isolated from SIV-infected animals. We anticipate that our findings will inform future research into macrophage-directed immunity across a variety of primate diseases. IMPORTANCE These findings highlight the functional and phenotypic heterogeneity of tissue macrophages in different anatomic sites and as a result of SIV infection. We believe that our data will lead to novel therapeutic interventions aimed at altering the proinflammatory capacity of tissue macrophages in progressively HIV-infected individuals.N onhuman primates (NHPs) serve as an ultimate model for studying some human diseases and development. NHPs share upwards of 90% genetic similarity to humans, exhibit a largely parallel developmental program, and mirror human anatomy and anatomic process (1). The zoonotic transmission of pathogens from NHPs to humans remains a significant concern and has been documented to include herpes simian B virus, Marburg virus, and simian immunodeficiency virus (SIV), the ancestral progenitor of human immunodeficiency virus (HIV). Despite the many evolutionarily conserved similarities between human and divergent NHP species, differences in disease outcome are apparent. Importantly, HIV type 1 (HIV-1) infection in humans and SIV infection in Asian macaques result in similar, severe disease progressions, while SIV infection in NHPs of African origin results in a nonpathogenic course of disease (2). Given the limited divergence exhibited between primate species, a complete dissection of immunological processes in NHP species will yield critical information regarding potential mechanisms of disease progression and remission in human patients.SIV infection in Asian macaques and HIV infection of humans are characterized by persistent immune activation that is attributable, in part, to damage to the gastrointestinal barrier and subsequent microbial translocation (3, 4). The gastrointestinal lumen is estimated to contain 10 14 commensal and potentially pathogenic microbes that are kept separate from the underlying tissu...

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Macrophages Accumulate in the Gut Mucosa of Untreated HIV-infected Patients

Cited by 72 publications

References 47 publications

Shift in Monocyte Apoptosis with Increasing Viral Load and Change in Apoptosis-Related ISG/Bcl2 Family Gene Expression in Chronically HIV-1-Infected Subjects

Shift in Monocyte Apoptosis with Increasing Viral Load and Change in Apoptosis-Related ISG/Bcl2 Family Gene Expression in Chronically HIV-1-Infected Subjects

Gastrointestinal Tract and the Mucosal Macrophage Reservoir in HIV Infection

Macrophages Are Phenotypically and Functionally Diverse across Tissues in Simian Immunodeficiency Virus-Infected and Uninfected Asian Macaques

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