Microbial translocation is a cause of systemic immune activation in chronic HIV infection

Brenchley, Jason M.; Price, David A.; Schacker, Timothy W.; Asher, Tedi E.; Silvestri, Guido; Rao, Srinivas S.; Kazzaz, Zachary; Bornstein, Ethan; Lambotte, Olivier; Altmann, Daniel M.; Blazar, Bruce R.; Rodrı́guez, Benigno; Teixeira-Johnson, Leia; Landay, Alan; Martin, Jeffrey N.; Hecht, Frederick M.; Picker, Louis J.; Lederman, Michael M.; Deeks, Steven G.; Douek, Daniel C.

doi:10.1038/nm1511

Cited by 3,099 publications

(3,063 citation statements)

References 46 publications

Supporting

123

Mentioning

2,821

Contrasting

Unclassified

Order By: Relevance

“…Brenchley et al 16 suggested that microbial translation, which is a consequence of severe damage to the gastrointestinal tract during HIV infection, might play a critical role in chronic immune activation. They found elevated plasma lipopolysaccharide (LPS) levels in HIV-1-infected individuals, which served as an indicator of microbial translocation.…”

Section: Discussionmentioning

confidence: 99%

Inhibitory effects of chloroquine on the activation of plasmacytoid dendritic cells in SIVmac239-infected Chinese rhesus macaques

Xia

Zhang

et al. 2012

Cell Mol Immunol

View full text Add to dashboard Cite

It is currently widely accepted that immune activation in HIV-infected individuals leads to a severe loss of CD4 1 T cells and the progression to AIDS. However, the underlying mechanism of this immune activation remains unclear. Experimental data suggest that the activation of plasmacytoid dendritic cells (pDCs) by plasma viremia may play a critical role in HIV-induced immune activation. In this study, we found that the level of immune activation was higher in the late phase of SIVmac239 infection compared with chronic infection, which suggests that immune activation might be related to disease progression in SIVmac239-infected non-human primate models. Our work also showed that chloroquine could effectively inhibit the activation of pDCs in vitro and in vivo. However, chloroquine treatment of SIVmac239-infected macaques had no significant influence on the Cellular composition of peripheral blood in these animals.

show abstract

Section: Discussionmentioning

confidence: 99%

Inhibitory effects of chloroquine on the activation of plasmacytoid dendritic cells in SIVmac239-infected Chinese rhesus macaques

Xia

Zhang

et al. 2012

Cell Mol Immunol

View full text Add to dashboard Cite

show abstract

“…With introduction of HAART, therefore, the patients on HAART with a slowly progressive dementia and incomplete virological control have been proposed (McArthur et al, 2003). Recently, Brenchley et al reported that plasma LPS levels are still higher in chronic HIV-infected patients with HAART than in the uninfected (Brenchley et al, 2006). Furthermore, HAART is often started when immune suppression first manifests.…”

Section: Discussionmentioning

confidence: 99%

Lipopolysaccharide-enhanced transcellular transport of HIV-1 across the blood-brain barrier is mediated by the p38 mitogen-activated protein kinase pathway

Dohgu

Banks

2008

Experimental Neurology

View full text Add to dashboard Cite

Chronic systemic inflammation in the late stage of human immunodeficiency virus type-1 (HIV-1) infection could increase neuroinvasion of infected monocytes and cell-free virus, causing an aggravation of neurological disorders in AIDS patients. We previously showed that the peripheral administration of lipopolysaccharide (LPS) enhanced the uptake across the blood-brain barrier (BBB) of the HIV-1 viral protein gp120. Brain microvessel endothelial cells are targets of LPS. Here, we investigated whether the direct interaction between LPS and the BBB also affected HIV-1 transport using primary mouse brain microvessel endothelial cells (BMECs). LPS produced a dose (1-100 μg/mL)-and time (0.5-4 hr)-dependent increase in HIV-1 transport and a decrease in transendothelial electrical resistance (TEER). Whereas indomethacin (cyclooxygenase inhibitor) and L-NAME (NO synthase inhibitor) did not affect the LPS-induced changes in HIV-1 transport or TEER, pentoxifylline (TNF-αinhibitor) attenuated the decrease in TEER induced by LPS, but not the LPSinduced increase in HIV-1 transport. LPS also increased the phosphorylation of p44/42 MAPK and p38 MAPK but not that of JNK. U0126 (p44/42 MAPK inhibitor) and SP600125 (JNK inhibitor) did not inhibit the LPS-induced increase in HIV-1 transport although U0126 attenuated the reduction in TEER. SB203580 (p38 MAPK inhibitor) inhibited the LPS-induced increase in HIV-1 transport without affecting TEER. Thus, LPS-enhanced HIV-1 transport is independent of changes in TEER and so is attributed to increased transcellular trafficking of HIV-1 across the BBB. These results show that LPS increases HIV-1 transcellular transport across the BBB by a pathway that is mediated by p38 MAPK phosphorylation in BMECs.

show abstract

“…14,15 Various clinical factors have been associated with impaired CD4 T-cell reconstitution following cART, including lower CD4 T-cell counts at initiation of cART, [16][17][18][19] being older at cART initiation 1,17,19,20 and higher levels of immune activation both before and while on cART as measured by T-cell activation markers (such as human leukocyte antigen (HLA)-DR þ CD38 þ expression). [21][22][23][24] Multiple host genetic factors have also been found to influence CD4 T-cell recovery. [25][26][27][28][29][30][31] We recently demonstrated by using a multivariable model that IL-7Ra haplotype-2 was a significant predictor of more rapid CD4 T-cell recovery following suppressive cART in an Australian-based largely Caucasian HIVinfected cohort.…”

Section: Introductionmentioning

confidence: 99%

The role of SNPs in the α-chain of the IL-7R gene in CD4+ T-cell recovery in HIV-infected African patients receiving suppressive cART

et al. 2011

View full text Add to dashboard Cite

We previously found an association between faster CD4 þ T-cell recovery in HIV-infected patients receiving combination antiretroviral therapy (cART) and interleukin-7 receptor-a (IL-7Ra) haplotype-2 in a predominantly Caucasian cohort. This study aims to determine whether this association was also significant in Africans. Patients were recruited from the Uganda AIDS Rural Treatment Outcomes (UARTO) cohort (n ¼ 352). We used survival analysis and linear mixed modelling (LMM) to determine factors associated with CD4 T-cell recovery. Eight IL-7Ra single-nucleotide polymorphisms (SNPs) were genotyped in both Africans and Caucasians (n ¼ 57). Soluble (s)IL-7Ra levels were measured by ELISA. In UARTO, IL-7Ra haplotype-2 was associated with slower CD4 T-cell recovery following cART by using survival analysis (P ¼ 0.020) and no association was found with LMM (P ¼ 0.958). The tagging-SNP for IL-7Ra haplotype-2 (rs6897932) was associated with decreased sIL-7Ra (Po0.001). The haplotypes for the IL-7Ra were significantly different in Africans and Caucasians. Using IL-7Ra genotypes we found slower CD4 T-cell recovery in UARTO patients was still associated with rs6897932 (P ¼ 0.009) and rs3194051 was associated with faster CD4 T-cell recovery (P ¼ 0.006). Unlike Caucasians, we did not demonstrate a significant association between IL-7Ra haplotype 2 and faster CD4 T-cell recovery in Africans. The IL-7Ra SNPs associated with CD4 T-cell recovery following cART differ in African and Caucasian cohorts.

show abstract

Microbial translocation is a cause of systemic immune activation in chronic HIV infection

Cited by 3,099 publications

References 46 publications

Inhibitory effects of chloroquine on the activation of plasmacytoid dendritic cells in SIVmac239-infected Chinese rhesus macaques

Inhibitory effects of chloroquine on the activation of plasmacytoid dendritic cells in SIVmac239-infected Chinese rhesus macaques

Lipopolysaccharide-enhanced transcellular transport of HIV-1 across the blood-brain barrier is mediated by the p38 mitogen-activated protein kinase pathway

The role of SNPs in the α-chain of the IL-7R gene in CD4+ T-cell recovery in HIV-infected African patients receiving suppressive cART

Contact Info

Product

Resources

About