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Transcriptome analysis of monocyte-HIV interactions

Rafael Van den Bergh, Eric Florence, Erika Vlieghe, Tom Boonefaes, Johan Grooten UGent, Erica Houthuys UGent, Huyen Thi Thanh Tran, Youssef Gali, Patrick De Baetselier and Guido Vanham, et al. (2010) RETROVIROLOGY. 7.
abstract
Background: During HIV infection and/or antiretroviral therapy (ART), monocytes and macrophages exhibit a wide range of dysfunctions which contribute significantly to HIV pathogenesis and therapy-associated complications. Nevertheless, the molecular components which contribute to these dysfunctions remain elusive. We therefore applied a parallel approach of genome-wide microarray analysis and focused gene expression profiling on monocytes from patients in different stages of HIV infection and/or ART to further characterise these dysfunctions. Results: Processes involved in apoptosis, cell cycle, lipid metabolism, proteasome function, protein trafficking and transcriptional regulation were identified as areas of monocyte dysfunction during HIV infection. Individual genes potentially contributing to these monocyte dysfunctions included several novel factors. One of these is the adipocytokine NAMPT/visfatin, which we show to be capable of inhibiting HIV at an early step in its life cycle. Roughly half of all genes identified were restored to control levels under ART, while the others represented a persistent dysregulation. Additionally, several candidate biomarkers (in particular CCL1 and CYP2C19) for the development of the abacavir hypersensitivity reaction were suggested. Conclusions: Previously described areas of monocyte dysfunction during HIV infection were confirmed, and novel themes were identified. Furthermore, individual genes associated with these dysfunctions and with ART-associated disorders were pinpointed. These genes form a useful basis for further functional studies concerning the contribution of monocytes/macrophages to HIV pathogenesis. One such gene, NAMPT/visfatin, represents a possible novel restriction factor for HIV. Background: Both macrophages and T lymphocyte subsets express the CD4 receptor and either the CXCR4 and/or the CCR5 coreceptor which confer susceptibility to infection with the Human Immunodeficiency Virus (HIV). Upon infection, CD4(+) T lymphocytes typically succumb to the cytopathic effect of the virus [1], and the gradual depletion of the CD4(+) T lymphocyte pool has been considered a hallmark of HIV infection and the development of the Acquired Immune Deficiency Syndrome (AIDS) since the early days of the HIV pandemic. Macrophages, on the other hand, do not tend to suffer from the cytopathic effects mediated by the virus [2,3], but instead develop a wide array of dysfunctions which contribute significantly to the pathogenesis of HIV infection. Despite the recognition of macrophage contribution to HIV pathogenesis early on in HIV research [4,5], most studies have focused and continue to focus on T lymphocyte depletion and/or dysfunction, and many of the molecular mechanisms underlying the macrophage dysfunction during HIV infection remain poorly characterised. Nevertheless, as pointed out by other authors [6], in the combination Antiretroviral Therapy (ART) era where viral suppression in T lymphocytes is increasingly more efficient, the understanding of the viral mechanisms in other reservoir cells such as macrophages becomes ever more crucial. Aberrant HIV-induced macrophage behaviour can be classified as relatively straightforward loss of function, such as reduced phagocytosis [7,8] and antigen presentation [9], or as more complex dysfunction. Such dysfunctions include a direct contribution to the establishment, spread and persistence of the infection: as long-living primary target cells of HIV with a wide-spread dissemination and a persistent failure to enter apoptosis upon infection [10,11], they represent an important cellular reservoir for the virus [12]. Additionally, macrophages exacerbate disease progression by contributing to T lymphocyte depletion: HIV infected macrophages have been documented to participate in the killing of uninfected CD4(+) and CD8(+) T lymphocytes, while at the same time protecting infected CD4+ T lymphocytes from apoptosis [13]. Furthermore, infected and uninfected macrophages can contribute to sustained chronic immune activation during HIV infection, e. g. through the perturbation of cytokine and chemokine networks [14-16]. With the acknowledged notion of chronic immune activation as a paradoxical driving force of immune suppression [17], this pro-inflammatory macrophage phenotype during HIV infection may be a crucial parameter in disease progression. Yet other macrophage dysfunctions are associated with more peripheral HIV- or ART-associated disorders such as atherosclerosis [18], lipodystrophy [19], and metabolic syndrome during HIV infection and/ or combination ART [20,21]. Monocytes, for their part, are much less permissive to infection with HIV, both in vitro [22] and in vivo, where estimates of infected circulating monocytes are consistently low [23,24]. Circulating monocytes represent the most accessible primary model for macrophage dysfunction during HIV infection, however, and are furthermore of sufficient importance to study in their own right. Infectious virus can be recovered from circulating monocytes, both in untreated patients [24] and in patients undergoing long-term successful combination ART [25]. Additionally, the circulating monocyte pool as a whole does seem to be affected during HIV infection, despite the low frequency of actually infected monocytes. Transcriptome studies, in particular, show a form of hybrid phenotype exhibiting both increased and decreased pro-inflammatory features [26,27]. This modulation of the non-infected monocyte population could be due to the virus itself through mechanisms which do not require direct infection [28], or to other factors contributing to (aberrant) immune activation occurring during HIV infection, such as perturbed cytokine networks [29] or other inflammatory stimulants [30]. Several key factors in the described dysregulated processes have been identified [18,31], but many molecular components remain elusive. Furthermore, other aspects of HIV and combination ART pathogenesis in which monocyte/macrophage dysfunction is involved may only now be emerging or remain yet to be discovered, in particular in view of the limited number of studies focussing on the monocyte response to ART [32]. In order to generate novel hypotheses rather than test pre-existing ones in the context of monocyte-HIV interactions, we performed a transcriptome analysis on monocyte samples from patients in different stages of HIV infection and/ or combination ART treatment, using a parallel approach of genome-wide microarray analysis and focused gene expression profiling to identify broad areas of monocyte dysfunction and to pinpoint genes which are potentially involved in one or several of these dysfunctions. In particular the factors which are exploited by the monocyte/macrophage to communicate with and/ or modulate other immune cells were of interest, as they represent a particularly relevant population [33,34] which is a primary target for intervention.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
ALVEOLAR MACROPHAGES, VIRAL REPLICATION, HIV-1-INFECTED MACROPHAGES, CELL-GROWTH, HUMAN MACROPHAGES, TUMOR-NECROSIS-FACTOR, COLONY-ENHANCING FACTOR, ACTIVE ANTIRETROVIRAL THERAPY, PERIPHERAL-BLOOD MONOCYTES, HUMAN-IMMUNODEFICIENCY-VIRUS
journal title
RETROVIROLOGY
Retrovirology
volume
7
article_number
53
pages
16 pages
Web of Science type
Article
Web of Science id
000280297100001
JCR category
VIROLOGY
JCR impact factor
5.236 (2010)
JCR rank
4/32 (2010)
JCR quartile
1 (2010)
ISSN
1742-4690
DOI
10.1186/1742-4690-7-53
language
English
UGent publication?
yes
classification
A1
copyright statement
I have retained and own the full copyright for this publication
id
1019404
handle
http://hdl.handle.net/1854/LU-1019404
date created
2010-08-09 12:05:44
date last changed
2012-06-26 14:32:05
@article{1019404,
  abstract     = {Background: During HIV infection and/or antiretroviral therapy (ART), monocytes and macrophages exhibit a wide range of dysfunctions which contribute significantly to HIV pathogenesis and therapy-associated complications. Nevertheless, the molecular components which contribute to these dysfunctions remain elusive. We therefore applied a parallel approach of genome-wide microarray analysis and focused gene expression profiling on monocytes from patients in different stages of HIV infection and/or ART to further characterise these dysfunctions.
Results: Processes involved in apoptosis, cell cycle, lipid metabolism, proteasome function, protein trafficking and transcriptional regulation were identified as areas of monocyte dysfunction during HIV infection. Individual genes potentially contributing to these monocyte dysfunctions included several novel factors. One of these is the adipocytokine NAMPT/visfatin, which we show to be capable of inhibiting HIV at an early step in its life cycle. Roughly half of all genes identified were restored to control levels under ART, while the others represented a persistent dysregulation. Additionally, several candidate biomarkers (in particular CCL1 and CYP2C19) for the development of the abacavir hypersensitivity reaction were suggested.
Conclusions: Previously described areas of monocyte dysfunction during HIV infection were confirmed, and novel themes were identified. Furthermore, individual genes associated with these dysfunctions and with ART-associated disorders were pinpointed. These genes form a useful basis for further functional studies concerning the contribution of monocytes/macrophages to HIV pathogenesis. One such gene, NAMPT/visfatin, represents a possible novel restriction factor for HIV. Background: Both macrophages and T lymphocyte subsets express the CD4 receptor and either the CXCR4 and/or the CCR5 coreceptor which confer susceptibility to infection with the Human Immunodeficiency Virus (HIV). Upon infection, CD4(+) T lymphocytes typically succumb to the cytopathic effect of the virus [1], and the gradual depletion of the CD4(+) T lymphocyte pool has been considered a hallmark of HIV infection and the development of the Acquired Immune Deficiency Syndrome (AIDS) since the early days of the HIV pandemic. Macrophages, on the other hand, do not tend to suffer from the cytopathic effects mediated by the virus [2,3], but instead develop a wide array of dysfunctions which contribute significantly to the pathogenesis of HIV infection. Despite the recognition of macrophage contribution to HIV pathogenesis early on in HIV research [4,5], most studies have focused and continue to focus on T lymphocyte depletion and/or dysfunction, and many of the molecular mechanisms underlying the macrophage dysfunction during HIV infection remain poorly characterised. Nevertheless, as pointed out by other authors [6], in the combination Antiretroviral Therapy (ART) era where viral suppression in T lymphocytes is increasingly more efficient, the understanding of the viral mechanisms in other reservoir cells such as macrophages becomes ever more crucial. Aberrant HIV-induced macrophage behaviour can be classified as relatively straightforward loss of function, such as reduced phagocytosis [7,8] and antigen presentation [9], or as more complex dysfunction. Such dysfunctions include a direct contribution to the establishment, spread and persistence of the infection: as long-living primary target cells of HIV with a wide-spread dissemination and a persistent failure to enter apoptosis upon infection [10,11], they represent an important cellular reservoir for the virus [12]. Additionally, macrophages exacerbate disease progression by contributing to T lymphocyte depletion: HIV infected macrophages have been documented to participate in the killing of uninfected CD4(+) and CD8(+) T lymphocytes, while at the same time protecting infected CD4+ T lymphocytes from apoptosis [13]. Furthermore, infected and uninfected macrophages can contribute to sustained chronic immune activation during HIV infection, e. g. through the perturbation of cytokine and chemokine networks [14-16]. With the acknowledged notion of chronic immune activation as a paradoxical driving force of immune suppression [17], this pro-inflammatory macrophage phenotype during HIV infection may be a crucial parameter in disease progression. Yet other macrophage dysfunctions are associated with more peripheral HIV- or ART-associated disorders such as atherosclerosis [18], lipodystrophy [19], and metabolic syndrome during HIV infection and/ or combination ART [20,21].
Monocytes, for their part, are much less permissive to infection with HIV, both in vitro [22] and in vivo, where estimates of infected circulating monocytes are consistently low [23,24]. Circulating monocytes represent the most accessible primary model for macrophage dysfunction during HIV infection, however, and are furthermore of sufficient importance to study in their own right. Infectious virus can be recovered from circulating monocytes, both in untreated patients [24] and in patients undergoing long-term successful combination ART [25]. Additionally, the circulating monocyte pool as a whole does seem to be affected during HIV infection, despite the low frequency of actually infected monocytes. Transcriptome studies, in particular, show a form of hybrid phenotype exhibiting both increased and decreased pro-inflammatory features [26,27]. This modulation of the non-infected monocyte population could be due to the virus itself through mechanisms which do not require direct infection [28], or to other factors contributing to (aberrant) immune activation occurring during HIV infection, such as perturbed cytokine networks [29] or other inflammatory stimulants [30].
Several key factors in the described dysregulated processes have been identified [18,31], but many molecular components remain elusive. Furthermore, other aspects of HIV and combination ART pathogenesis in which monocyte/macrophage dysfunction is involved may only now be emerging or remain yet to be discovered, in particular in view of the limited number of studies focussing on the monocyte response to ART [32]. In order to generate novel hypotheses rather than test pre-existing ones in the context of monocyte-HIV interactions, we performed a transcriptome analysis on monocyte samples from patients in different stages of HIV infection and/ or combination ART treatment, using a parallel approach of genome-wide microarray analysis and focused gene expression profiling to identify broad areas of monocyte dysfunction and to pinpoint genes which are potentially involved in one or several of these dysfunctions. In particular the factors which are exploited by the monocyte/macrophage to communicate with and/ or modulate other immune cells were of interest, as they represent a particularly relevant population [33,34] which is a primary target for intervention.},
  articleno    = {53},
  author       = {Van den Bergh, Rafael and Florence, Eric and Vlieghe, Erika and Boonefaes, Tom and Grooten, Johan and Houthuys, Erica and Tran, Huyen Thi Thanh and Gali, Youssef and De Baetselier, Patrick and Vanham, Guido and Raes, Geert},
  issn         = {1742-4690},
  journal      = {RETROVIROLOGY},
  keyword      = {ALVEOLAR MACROPHAGES,VIRAL REPLICATION,HIV-1-INFECTED MACROPHAGES,CELL-GROWTH,HUMAN MACROPHAGES,TUMOR-NECROSIS-FACTOR,COLONY-ENHANCING FACTOR,ACTIVE ANTIRETROVIRAL THERAPY,PERIPHERAL-BLOOD MONOCYTES,HUMAN-IMMUNODEFICIENCY-VIRUS},
  language     = {eng},
  pages        = {16},
  title        = {Transcriptome analysis of monocyte-HIV interactions},
  url          = {http://dx.doi.org/10.1186/1742-4690-7-53},
  volume       = {7},
  year         = {2010},
}

Chicago
Van den Bergh, Rafael, Eric Florence, Erika Vlieghe, Tom Boonefaes, Johan Grooten, Erica Houthuys, Huyen Thi Thanh Tran, et al. 2010. “Transcriptome Analysis of monocyte-HIV Interactions.” Retrovirology 7.
APA
Van den Bergh, R., Florence, E., Vlieghe, E., Boonefaes, T., Grooten, J., Houthuys, E., Tran, H. T. T., et al. (2010). Transcriptome analysis of monocyte-HIV interactions. RETROVIROLOGY, 7.
Vancouver
1.
Van den Bergh R, Florence E, Vlieghe E, Boonefaes T, Grooten J, Houthuys E, et al. Transcriptome analysis of monocyte-HIV interactions. RETROVIROLOGY. 2010;7.
MLA
Van den Bergh, Rafael, Eric Florence, Erika Vlieghe, et al. “Transcriptome Analysis of monocyte-HIV Interactions.” RETROVIROLOGY 7 (2010): n. pag. Print.