Liver macrophage-associated inflammation correlates with SIV burden and is substantially reduced following cART

Bridget S. Fisher, Richard R. Green, Rachel R. Brown, Matthew P. Wood, Tiffany Hensley-McBain, Cole Fisher, Jean Chang, Andrew D. Miller, William J. Bosche, Jeffrey D. Lifson, Maud Mavigner, Charlene J. Miller, Michael Gale, Guido Silvestri, Ann Chahroudi, Nichole Klatt, Donald L. Sodora

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Liver disease is a leading contributor to morbidity and mortality during HIV infection, despite the use of combination antiretroviral therapy (cART). The precise mechanisms of liver disease during HIV infection are poorly understood partially due to the difficulty in obtaining human liver samples as well as the presence of confounding factors (e.g. hepatitis co-infection, alcohol use). Utilizing the simian immunodeficiency virus (SIV) macaque model, a controlled study was conducted to evaluate the factors associated with liver inflammation and the impact of cART. We observed an increase in hepatic macrophages during untreated SIV infection that was associated with a number of inflammatory and fibrosis mediators (TNFα, CCL3, TGFβ). Moreover, an upregulation in the macrophage chemoattractant factor CCL2 was detected in the livers of SIV-infected macaques that coincided with an increase in the number of activated CD16+ monocyte/macrophages and T cells expressing the cognate receptor CCR2. Expression of Mac387 on monocyte/macrophages further indicated that these cells recently migrated to the liver. The hepatic macrophage and T cell levels strongly correlated with liver SIV DNA levels, and were not associated with the levels of 16S bacterial DNA. Utilizing in situ hybridization, SIV-infected cells were found primarily within portal triads, and were identified as T cells. Microarray analysis identified a strong antiviral transcriptomic signature in the liver during SIV infection. In contrast, macaques treated with cART exhibited lower levels of liver macrophages and had a substantial, but not complete, reduction in their inflammatory profile. In addition, residual SIV DNA and bacteria 16S DNA were detected in the livers during cART, implicating the liver as a site on-going immune activation during antiretroviral therapy. These findings provide mechanistic insights regarding how SIV infection promotes liver inflammation through macrophage recruitment, with implications for in HIV-infected individuals.

Original languageEnglish (US)
Article numbere1006871
JournalPLoS Pathogens
Volume14
Issue number2
DOIs
StatePublished - Feb 1 2018
Externally publishedYes

Fingerprint

Simian Immunodeficiency Virus
Macrophages
Inflammation
Liver
Macaca
Virus Diseases
Therapeutics
T-Lymphocytes
HIV Infections
Liver Diseases
Monocytes
DNA
CCR2 Receptors
Bacterial DNA
Chemotactic Factors
Microarray Analysis
Coinfection
Hepatitis
In Situ Hybridization
Antiviral Agents

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Immunology
  • Molecular Biology
  • Genetics
  • Virology

Cite this

Fisher, B. S., Green, R. R., Brown, R. R., Wood, M. P., Hensley-McBain, T., Fisher, C., ... Sodora, D. L. (2018). Liver macrophage-associated inflammation correlates with SIV burden and is substantially reduced following cART. PLoS Pathogens, 14(2), [e1006871]. https://doi.org/10.1371/journal.ppat.1006871

Liver macrophage-associated inflammation correlates with SIV burden and is substantially reduced following cART. / Fisher, Bridget S.; Green, Richard R.; Brown, Rachel R.; Wood, Matthew P.; Hensley-McBain, Tiffany; Fisher, Cole; Chang, Jean; Miller, Andrew D.; Bosche, William J.; Lifson, Jeffrey D.; Mavigner, Maud; Miller, Charlene J.; Gale, Michael; Silvestri, Guido; Chahroudi, Ann; Klatt, Nichole; Sodora, Donald L.

In: PLoS Pathogens, Vol. 14, No. 2, e1006871, 01.02.2018.

Research output: Contribution to journalArticle

Fisher, BS, Green, RR, Brown, RR, Wood, MP, Hensley-McBain, T, Fisher, C, Chang, J, Miller, AD, Bosche, WJ, Lifson, JD, Mavigner, M, Miller, CJ, Gale, M, Silvestri, G, Chahroudi, A, Klatt, N & Sodora, DL 2018, 'Liver macrophage-associated inflammation correlates with SIV burden and is substantially reduced following cART', PLoS Pathogens, vol. 14, no. 2, e1006871. https://doi.org/10.1371/journal.ppat.1006871
Fisher, Bridget S. ; Green, Richard R. ; Brown, Rachel R. ; Wood, Matthew P. ; Hensley-McBain, Tiffany ; Fisher, Cole ; Chang, Jean ; Miller, Andrew D. ; Bosche, William J. ; Lifson, Jeffrey D. ; Mavigner, Maud ; Miller, Charlene J. ; Gale, Michael ; Silvestri, Guido ; Chahroudi, Ann ; Klatt, Nichole ; Sodora, Donald L. / Liver macrophage-associated inflammation correlates with SIV burden and is substantially reduced following cART. In: PLoS Pathogens. 2018 ; Vol. 14, No. 2.
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abstract = "Liver disease is a leading contributor to morbidity and mortality during HIV infection, despite the use of combination antiretroviral therapy (cART). The precise mechanisms of liver disease during HIV infection are poorly understood partially due to the difficulty in obtaining human liver samples as well as the presence of confounding factors (e.g. hepatitis co-infection, alcohol use). Utilizing the simian immunodeficiency virus (SIV) macaque model, a controlled study was conducted to evaluate the factors associated with liver inflammation and the impact of cART. We observed an increase in hepatic macrophages during untreated SIV infection that was associated with a number of inflammatory and fibrosis mediators (TNFα, CCL3, TGFβ). Moreover, an upregulation in the macrophage chemoattractant factor CCL2 was detected in the livers of SIV-infected macaques that coincided with an increase in the number of activated CD16+ monocyte/macrophages and T cells expressing the cognate receptor CCR2. Expression of Mac387 on monocyte/macrophages further indicated that these cells recently migrated to the liver. The hepatic macrophage and T cell levels strongly correlated with liver SIV DNA levels, and were not associated with the levels of 16S bacterial DNA. Utilizing in situ hybridization, SIV-infected cells were found primarily within portal triads, and were identified as T cells. Microarray analysis identified a strong antiviral transcriptomic signature in the liver during SIV infection. In contrast, macaques treated with cART exhibited lower levels of liver macrophages and had a substantial, but not complete, reduction in their inflammatory profile. In addition, residual SIV DNA and bacteria 16S DNA were detected in the livers during cART, implicating the liver as a site on-going immune activation during antiretroviral therapy. These findings provide mechanistic insights regarding how SIV infection promotes liver inflammation through macrophage recruitment, with implications for in HIV-infected individuals.",
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