Microbial Translocation is a Cause of Systemic Immune Activation in Chronic HIV Infection

Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
Nature Medicine (Impact Factor: 27.36). 12/2006; 12(12):1365-71. DOI: 10.1038/nm1511
Source: PubMed


Chronic activation of the immune system is a hallmark of progressive HIV infection and better predicts disease outcome than plasma viral load, yet its etiology remains obscure. Here we show that circulating microbial products, probably derived from the gastrointestinal tract, are a cause of HIV-related systemic immune activation. Circulating lipopolysaccharide, which we used as an indicator of microbial translocation, was significantly increased in chronically HIV-infected individuals and in simian immunodeficiency virus (SIV)-infected rhesus macaques (P <or= 0.002). We show that increased lipopolysaccharide is bioactive in vivo and correlates with measures of innate and adaptive immune activation. Effective antiretroviral therapy seemed to reduce microbial translocation partially. Furthermore, in nonpathogenic SIV infection of sooty mangabeys, microbial translocation did not seem to occur. These data establish a mechanism for chronic immune activation in the context of a compromised gastrointestinal mucosal surface and provide new directions for therapeutic interventions that modify the consequences of acute HIV infection.

Download full-text


Available from: Louis J Picker, Oct 08, 2015
300 Reads
  • Source
    • "This T-cell subset is known to contribute to the recruitment of neutrophils (Ye et al., 2001) which produce antimicrobial and anti-HIV-1 molecules such as defensins (Chang and Klotman, 2004; Chang et al., 2005; Wu et al., 2005), and remove bacteria and products thereof by phagocytosis (Dobmeyer et al., 1995). Neutrophils in GALT appear to slow the progression of HIV- 1 pathogenesis by opposing microbial translocation (Ancuta et al., 2008; Brenchley et al., 2006). Furthermore, the ability of neutrophils to undergo rapid apoptosis is important for the resolution of inflammation (El Kebir and Filep, 2010; El Kebir et al., 2012; McGrath et al., 2011), and our present results indicate that exosomes released from HIV-1-infected cells likely interfere with this process. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Exosomes are extracellular vesicles (EVs) that play a role in intercellular communication. Stimulation of dendritic cells by the HIV-1 virus triggers their release. HIV-1 binds to dendritic cells via dendritic cell immunoreceptor (DCIR). This study shows that inhibiting the binding to DCIR significantly decreases exosome release by HIV-1-pulsed dendritic cells. In addition, exosome release from Raji-CD4 expressing DCIR cells stimulated by anti-DCIR or HIV-1 is decreased when the immunoreceptor tyrosine-based inhibition motif (ITIM) signaling motif of DCIR is mutated. Unlike the EVs released from Raji-CD4-DCIR cells after antibody stimulation, those released from HIV-1-infected cells contain the pro-apoptotic protein DAP-3. Furthermore, EVs from HIV-1 pulsed dendritic cells increase spontaneous apoptosis in uninfected CD4 T lymphocytes while they decrease it in neutrophils. This study describes for the first time that DCIR plays a role in the release of exosomes strengthening the importance of this receptor and EVs/exosomes in HIV-1 pathogenesis. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Virology 10/2015; 484:103-112. DOI:10.1016/j.virol.2015.05.013 · 3.32 Impact Factor
  • Source
    • "In line with this, low levels of immune activation were observed in chronically infected natural hosts of SIV, such as African green monkeys and Sooty mangabeys who do not progress to diseases despite high levels of virus replication (Pandrea et al., 2008; Silvestri et al., 2003). Microbial translocation from the intestinal lumen to the systemic circulation appears to be a key factor underlying the chronic immune activation, and it is supposed to be the consequence of intestinal mucosal barrier dysfunction (Brenchley et al., 2006; Klatt et al., 2012). However, the underlying mechanisms such as the causal relationships between virus infection , intestinal mucosal barrier dysfunction and translocation of microbes and microbial products, and when and how the earliest gut barrier dysfunction occurred have not been completely understood. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background Mucosal barrier dysfunction might play a key role in HIV/AIDS, yet the early effects of HIV-1 on intestinal mucosal barrier, especially tight junctions (TJ) have not been well addressed. Aims To investigate the effects of acute HIV-1 infection on the expression of intestinal IL-17A and TJ-associated genes using an NHP-AIDS model. Methods TaqMan probe real-time RT-PCR methods were established and claudin-1, claudin-3, occludin and zonula occluden-1 (ZO-1) mRNA levels in the duodenal biopsies of rhesus macaques collected before and after rectal exposures to SHIV-SF162P4 were examined and compared with that of IL-17A, IL-6, TGF-β, RORγt, T-bet, Foxp3 and GATA-3. Results The mRNA levels of TJ-associated genes were statistically significantly reduced soon after viral exposures and the mRNA levels of claudin-1, occludin and ZO-1 in viral positive tissues (from Group I) were lower than that in viral negative tissues (from Group II) after viral exposure. IL-17A mRNA levels were also decreased and positively correlated with the mRNA levels of the TJ-associated genes after viral exposure or infection, although the levels of IL-6, TGF-β and RORγt mRNA showed no statistical difference. The levels of GATA-3 mRNA in tissues collected before viral exposure were statistically different between Group I and Group II animals. The balance between T-bet and GATA-3 mRNA levels in Group II was markedly altered and statistically significantly different from that in Group I. Conclusions Acute SHIV, and by extension HIV infection could affect the expression of TJ-associated genes, probably through IL-17A and other immune alterations.
    Experimental and Molecular Pathology 10/2014; 43(5). DOI:10.1016/j.yexmp.2014.07.007 · 2.71 Impact Factor
  • Source
    • "Early gut mucosal destruction in HIV infection results in microbial translocation and higher microbial products in the circulation that are supposed to be partially responsible of HIV-associated immune activation that persists despite the introduction of the antiretroviral treatment [26]. A recent study has shown an increase in mucosal macrophages in HIV naïve patients due to enhanced trafficking of blood monocytes in the gut but with lower phagocytic activity [27]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Introduction Monotherapy with protease-inhibitors (MPI) may be an alternative to cART for HIV treatment. We assessed the impact of this strategy on immune activation, bacterial translocation and inflammation. Methods We performed a cross-sectional study comparing patients on successful MPI (n=40) with patients on cART (n=20). Activation, senescence, exhaustion and differentiation stage in CD4+ and CD8+ T lymphocyte subsets, markers of monocyte activation, microbial translocation, inflammation, coagulation and low-level viremia were assessed. Results CD4+ or CD8+ T lymphocyte subset parameters were not significantly different between both groups. Conversely, as compared with triple cART, MPI patients showed a higher proportion of activated monocytes (CD14+ CD16−CD163+ cells, p=0.031), soluble markers of monocyte activation (sCD14 p=0.004, sCD163 p=0.002), microbial translocation (lipopolysaccharide (LPS)-binding protein; LBP p=0.07), inflammation (IL-6 p=0.04) and low-level viremia (p=0.035). In a multivariate model, a higher level of CD14+ CD16−CD163+ cells and sCD14, and presence of very low-level viremia were independently associated with MPI. Monocyte activation was independently associated with markers of inflammation (IL-6, p=0.006), microbial translocation (LBP, p=0.01) and low-level viremia (p=0.01). Conclusions Patients on MPI showed a higher level of monocyte activation than patients on standard therapy. Microbial translocation and low-level viremia were associated with the high level of monocyte activation observed in patients on MPI. The long-term clinical consequences of these findings should be assessed.
    Journal of the International AIDS Society 09/2014; 17(1):19246. DOI:10.7448/IAS.17.1.19246 · 5.09 Impact Factor
Show more