Papasavvas, E. et al. Delayed loss of control of plasma lipopolysaccharide levels after therapy interruption in chronically HIV-1-infected patients. AIDS 23, 369-375

The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
AIDS (London, England) (Impact Factor: 5.55). 01/2009; 23(3):369-75. DOI: 10.1097/QAD.0b013e32831e9c76
Source: PubMed


Increased circulating levels of lipopolysaccharide (LPS) have been demonstrated in HIV-1-infected progressors. We investigated the effect of antiretroviral therapy (ART) interruptions on plasma LPS levels.
Overall, 77 individuals participated in this study (51 HIV-positive and 26 healthy). Ten out of 51 HIV-positive participants were viremic ART-naive patients and 41 out of 51 were chronically suppressed patients on ART (three or more drugs, CD4 cell count more than 400 cells/microl, HIV-1 RNA less than 500 copies/ml for more than 8 months, less than 50 copies/ml at recruitment) undergoing therapy interruption. The limulus amebocyte assay was used to measure plasma LPS levels; enzyme-linked immunosorbent assay to measure plasma levels of endotoxin-core antibodies (EndoCAb), soluble (s)CD14, LPS-binding protein and IFN-alpha; immunoblotting to measure plasma gelsolin levels; and same day whole blood flow cytometry to measure levels of T-cell-activation markers (CD8/CD38, CD8/HLA-DR and CD3/CD95).
Increases in viremia and T-cell-activation markers were observed during therapy interruptions. During short-term therapy interruptions of less than 12 weeks, no change in LPS levels was found, whereas negative associations between viral load and LPS levels (Spearman's Rho = -0.612, P = 0.0152), viral load and EndoCAb change (DeltaEndoCAb, correlation = -0.502, P = 0.0204), and between DeltaLPS and DeltaEndoCAb (correlation = -0.851, P = 0.0073) were observed. In contrast, increased LPS (P = 0.0171) and sCD14 (P < 0.0001) levels were observed during long-term therapy interruption of more than 12 weeks compared with levels during ART, together with no association between LPS and viral load or EndoCAb. No association between immune activation and LPS was evident at any time point.
Increased plasma LPS levels were observed only after more than 12 weeks of ART interruption, despite presence of LPS-controlling host mechanisms.

Download full-text


Available from: Paul Janmey,
  • Source
    • "Wallet et al. (Wallet et al. 2010) showed in paediatric patients that microbial translocation is associated with persistent monocyte/macrophage activation, independently of viral replication or T cell activation. Papasavvas et al. (Papasavvas et al. 2009 "
    [Show abstract] [Hide abstract]
    ABSTRACT: Contributory factors to HIV-associated neurocognitive disorders (HAND) have been shown to include age, co-morbid infections, medication toxicity, virological, genetic and vascular mechanisms, as well as microbial translocation of lipopolysaccharide (LPS), which is suspected to trigger monocyte activation and increase trafficking of infected cells into the brain. In this study, our aim was to assess the degree of neurocognitive impairment in a group of randomly selected HIV-infected patients and investigate potential risk factors, including LPS plasma levels. Furthermore, we evaluated the relevance of LPS as a potential marker for screening patients with mild neurocognitive impairment. LPS plasma levels were compared among patients with HAND and those with no HAND. As LPS has also been shown to be elevated in hepatitis C co-infection, the analysis was stratified according to the presence or not of hepatitis C virus (HCV) co-infection. Differences between groups were evaluated using chi-square tests and Kruskal-Wallis non-parametric tests. Stepwise logistic regression was performed to identify independent risk factors for HAND in the subgroups of HCV-positive and negative patients. A p value <0.05 was considered significant. Analyses were conducted using SPSS® software. From December 2007 to July 2009, 179 patients were tested (mean age 44, 73 % male, 87 % on treatment, 30 % HCV co-infected, median CD4 504/ml and 67 % with viral load below 40 copies/ml). HAND was identified in 40/179 patients (22 %), the majority displaying asymptomatic neurocognitive impairment or mild neurocognitive disorder. Univariate analysis showed that age, illicit drug use, hepatitis C co-infection, prior AIDS-defining events, CD4/CD8 ratio and LPS plasma levels were significantly associated with HAND. The median LPS level was 98.2 pg/ml in the non-HAND group versus 116.1 pg/ml in the HAND group (p < 0.014). No differences were found in LPS values between subgroups of impairment. There was a clear association between LPS levels and HAND in the HCV-positive group (p = 0.036), while there was none in the HCV-negative group (p = 0.502). No difference in degree of hepatic fibrosis was found between the HAND and non-HAND groups. In conclusion, LPS levels were associated with HAND in the HCV-positive group, while, in the HCV-negative group, age and pro-viral DNA were the only variables independently associated with HAND. There was no difference in degree of liver disease as predicted by score of fibrosis between HAND and non-HAND groups. The role of HCV co-infection and higher LPS levels in the pathogenesis of HAND in patients with viral suppression on treatment requires further investigation.
    Journal of NeuroVirology 07/2013; 19(4). DOI:10.1007/s13365-013-0181-y · 2.60 Impact Factor
  • Source
    • "Moreover, two recent works did not show any relationship between microbial translocation and T-cell immune activation, in HIV-infected children on successful cART for Pilakka-Kanthikeel et al. [16] and in patients interrupting treatment for Papasavvas et al. [17]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: BACKGROUND: Recent observational studies suggest a role for lipopolysaccharide (LPS) as a marker of immune activation in HIV-infected patients, with potential repercussions on the effectiveness of antiretroviral regimens.ObjectA systematic review of LPS as a marker of immune activation in HIV-1 infected patients. DATA SOURCES: MEDLINE register of articles and international conference proceedings. REVIEW METHODS: Case--control studies comparing the role of plasma LPS as a marker of immune activation in HIV-infected patients versus HIV negative subjects.Data synthesisTwo hundred and six articles were selected using MEDLINE, plus 51 studies presented at international conferences. Plasma LPS is a marker of immune activation in HIV-infected patients, determining the entry of central memory CD4+ T cells into the replication cycle and finally generating cell death. Plasma LPS probably results from immune-mediated alterations of the intestinal barrier, which can occur soon after HIV seroconversion. LPS is a likely marker of disease progression, as it drives chronic monocyte activation, and some studies suggest that hyperexpression of CCR5 receptors, related to LPS plasma levels, could be responsible for monocyte trafficking in the brain compartment and for the appearance of HIV-associated neurocognitive disorders. Long-term combination antiretroviral therapy (cART) generally reduces LPS concentrations, but rarely to the same levels as in the control group. This phenomenon probably depends on ongoing but incomplete repair of the mucosal barrier. Only in patients achieving maximal viral suppression (i.e. viral load < 2.5 cp/ml) are LPS levels comparable to healthy donors. In successfully treated patients who did not restore CD4+ T cells, one hypothesis is that the degree of residual microbial translocation, measured by LPS, alters the turnover of CD4+ T cells. CONCLUSIONS: LPS is a marker of microbial translocation, responsible for chronic immune activation in HIV-infected patients. Even in successfully treated patients, LPS values are rarely normal. Several studies suggest a role for LPS as a negative predictive marker of immune restoration in patients with blunted CD4 T cell gain.
    Virology Journal 08/2012; 9(1):174. DOI:10.1186/1743-422X-9-174 · 2.18 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Why and how HIV makes people sick is highly debated. Recent evidence implicates heightened immune activation due to breakdown of the gastrointestinal barrier as a determining factor of lentiviral pathogenesis. HIV-mediated loss of Th17 cells from the gut-associated lymphoid tissue (GALT) impairs mucosal integrity and innate defense mechanisms against gut microbes. Translocation of microbial products from the gut, in turn, correlates with increased immune activation in chronic HIV infection and may further damage the immune system by increasing viral and activation-induced T cell death, by reducing T cell reconstitution due to tissue scarring, and by impairing the function of other cell types, such as gammadelta T cells and epithelial cells. Maintaining a healthy GALT may be the key to reducing the pathogenic potential of HIV.
    Seminars in Immunopathology 06/2009; 31(2):257-66. DOI:10.1007/s00281-009-0158-3 · 7.75 Impact Factor
Show more