Liver macrophage-associated inflammation correlates with SIV burden and is substantially reduced following cART.
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...
Main Authors: | , , , , , , , , , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Public Library of Science (PLoS)
2018-02-01
|
Series: | PLoS Pathogens |
Online Access: | https://doi.org/10.1371/journal.ppat.1006871 |
id |
doaj-d953b7a3ce3c4ce5924eb5d89c356efe |
---|---|
record_format |
Article |
spelling |
doaj-d953b7a3ce3c4ce5924eb5d89c356efe2021-04-21T17:44:03ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742018-02-01142e100687110.1371/journal.ppat.1006871Liver macrophage-associated inflammation correlates with SIV burden and is substantially reduced following cART.Bridget S FisherRichard R GreenRachel R BrownMatthew P WoodTiffany Hensley-McBainCole FisherJean ChangAndrew D MillerWilliam J BoscheJeffrey D LifsonMaud MavignerCharlene J MillerMichael GaleGuido SilvestriAnn ChahroudiNichole R KlattDonald L SodoraLiver 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.https://doi.org/10.1371/journal.ppat.1006871 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
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 R Klatt Donald L Sodora |
spellingShingle |
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 R Klatt Donald L Sodora Liver macrophage-associated inflammation correlates with SIV burden and is substantially reduced following cART. PLoS Pathogens |
author_facet |
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 R Klatt Donald L Sodora |
author_sort |
Bridget S Fisher |
title |
Liver macrophage-associated inflammation correlates with SIV burden and is substantially reduced following cART. |
title_short |
Liver macrophage-associated inflammation correlates with SIV burden and is substantially reduced following cART. |
title_full |
Liver macrophage-associated inflammation correlates with SIV burden and is substantially reduced following cART. |
title_fullStr |
Liver macrophage-associated inflammation correlates with SIV burden and is substantially reduced following cART. |
title_full_unstemmed |
Liver macrophage-associated inflammation correlates with SIV burden and is substantially reduced following cART. |
title_sort |
liver macrophage-associated inflammation correlates with siv burden and is substantially reduced following cart. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS Pathogens |
issn |
1553-7366 1553-7374 |
publishDate |
2018-02-01 |
description |
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. |
url |
https://doi.org/10.1371/journal.ppat.1006871 |
work_keys_str_mv |
AT bridgetsfisher livermacrophageassociatedinflammationcorrelateswithsivburdenandissubstantiallyreducedfollowingcart AT richardrgreen livermacrophageassociatedinflammationcorrelateswithsivburdenandissubstantiallyreducedfollowingcart AT rachelrbrown livermacrophageassociatedinflammationcorrelateswithsivburdenandissubstantiallyreducedfollowingcart AT matthewpwood livermacrophageassociatedinflammationcorrelateswithsivburdenandissubstantiallyreducedfollowingcart AT tiffanyhensleymcbain livermacrophageassociatedinflammationcorrelateswithsivburdenandissubstantiallyreducedfollowingcart AT colefisher livermacrophageassociatedinflammationcorrelateswithsivburdenandissubstantiallyreducedfollowingcart AT jeanchang livermacrophageassociatedinflammationcorrelateswithsivburdenandissubstantiallyreducedfollowingcart AT andrewdmiller livermacrophageassociatedinflammationcorrelateswithsivburdenandissubstantiallyreducedfollowingcart AT williamjbosche livermacrophageassociatedinflammationcorrelateswithsivburdenandissubstantiallyreducedfollowingcart AT jeffreydlifson livermacrophageassociatedinflammationcorrelateswithsivburdenandissubstantiallyreducedfollowingcart AT maudmavigner livermacrophageassociatedinflammationcorrelateswithsivburdenandissubstantiallyreducedfollowingcart AT charlenejmiller livermacrophageassociatedinflammationcorrelateswithsivburdenandissubstantiallyreducedfollowingcart AT michaelgale livermacrophageassociatedinflammationcorrelateswithsivburdenandissubstantiallyreducedfollowingcart AT guidosilvestri livermacrophageassociatedinflammationcorrelateswithsivburdenandissubstantiallyreducedfollowingcart AT annchahroudi livermacrophageassociatedinflammationcorrelateswithsivburdenandissubstantiallyreducedfollowingcart AT nicholerklatt livermacrophageassociatedinflammationcorrelateswithsivburdenandissubstantiallyreducedfollowingcart AT donaldlsodora livermacrophageassociatedinflammationcorrelateswithsivburdenandissubstantiallyreducedfollowingcart |
_version_ |
1714665855620481024 |