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Impact of HMGB1/TLR Ligand Complexes on HIV-1 Replication: Possible Role for Flagellin during HIV-1 Infection.

Nowak P, Abdurahman S, Lindkvist A, Troseid M, Sönnerborg A - Int J Microbiol (2012)

Bottom Line: Moreover, the stimulatory effect of necrotic extract was inhibited by depletion of HMGB1.Elevated levels of anti-flagellin antibodies were present in plasma from HIV-1-infected patients and significantly decreased during 2 years of antiretroviral therapy.Conclusions.

View Article: PubMed Central - PubMed

Affiliation: Department of Infectious Diseases, Institution of Medicine, Karolinska University Hospital and Karolinska Institutet, 14186 Stockholm, Sweden.

ABSTRACT
Objective. We hypothesized that HMGB1 in complex with bacterial components, such as flagellin, CpG-ODN, and LPS, promotes HIV-1 replication. Furthermore, we studied the levels of antiflagellin antibodies during HIV-1-infection. Methods. Chronically HIV-1-infected U1 cells were stimulated with necrotic extract/recombinant HMGB1 in complex with TLR ligands or alone. HIV-1 replication was estimated by p24 antigen in culture supernatants 48-72 hours after stimulation. The presence of systemic anti-flagellin IgG was determined in 51 HIV-1-infected patients and 19 controls by immunoblotting or in-house ELISA. Results. Flagellin, LPS, and CpG-ODN induced stronger HIV-1 replication when incubated together with necrotic extract or recombinant HMGB1 than activation by any of the compounds alone. Moreover, the stimulatory effect of necrotic extract was inhibited by depletion of HMGB1. Elevated levels of anti-flagellin antibodies were present in plasma from HIV-1-infected patients and significantly decreased during 2 years of antiretroviral therapy. Conclusions. Our findings implicate a possible role of HGMB1-bacterial complexes, as a consequence of microbial translocation and cell necrosis, for immune activation in HIV-1 pathogenesis. We propose that flagellin is an important microbial product, that modulates viral replication and induces adaptive immune responses in vivo.

No MeSH data available.


Related in: MedlinePlus

Elevated levels of anti-flagellin IgG are reduced during ART. Plasma levels (OD) of anti-flagellin IgG (a), ratio anti-flagellin IgG/total IgG (b), and total IgG (c) in healthy controls, HIV-1-infected individuals before (= naïve) and after two years of ART (antiretroviral therapy). The plasma samples were diluted 1:1000. The data are presented as median 25–75 interquartile range and total range. P values refer to intergroup differences.
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fig5: Elevated levels of anti-flagellin IgG are reduced during ART. Plasma levels (OD) of anti-flagellin IgG (a), ratio anti-flagellin IgG/total IgG (b), and total IgG (c) in healthy controls, HIV-1-infected individuals before (= naïve) and after two years of ART (antiretroviral therapy). The plasma samples were diluted 1:1000. The data are presented as median 25–75 interquartile range and total range. P values refer to intergroup differences.

Mentions: Furthermore, we used the anti-flagellin ELISA to evaluate the levels of flagellin IgG in plasma of HIV-1-infected patients before and after two years of ART. At baseline significantly elevated levels of flagellin antibodies were found in HIV-1-infected patients as compared to controls (P < 0.001) (Figure 5(a)). This difference persisted (P < 0.001) when the flagellin antibodies were adjusted to the total IgG (Figure 5(b)), suggesting that the elevation of flagellin antibodies was not due to hypergammaglobulinemia. Moreover, analysis of antimeasles antibodies in 10 patients with severe immune deficiency (CD4+ T-cell counts ≤ 200) supported that the elevation of the flagellin antibodies was not caused by polyclonal activation Supplementary Table 1 (see supplementary material available online at doi:10.1155/2012/263836). The levels of flagellin IgG, total IgG, and the ratio flagellin IgG/total IgG were significantly reduced after two years of ART for the whole group (P < 0.001, P = 0.03, and P < 0.001, resp. Figures 5(a)–5(c)). Additionally a significant reduction of flagellin IgG levels was observed also when the patients were subdivided into those with successful ART and the nonresponders who had remaining low levels of viral replication two years after initiating the ART (P = 0.009; P = 0.001, resp.). The total IgG levels after ART did not decrease in nonresponders as they did in successfully treated patients (P < 0.001) (data not shown).


Impact of HMGB1/TLR Ligand Complexes on HIV-1 Replication: Possible Role for Flagellin during HIV-1 Infection.

Nowak P, Abdurahman S, Lindkvist A, Troseid M, Sönnerborg A - Int J Microbiol (2012)

Elevated levels of anti-flagellin IgG are reduced during ART. Plasma levels (OD) of anti-flagellin IgG (a), ratio anti-flagellin IgG/total IgG (b), and total IgG (c) in healthy controls, HIV-1-infected individuals before (= naïve) and after two years of ART (antiretroviral therapy). The plasma samples were diluted 1:1000. The data are presented as median 25–75 interquartile range and total range. P values refer to intergroup differences.
© Copyright Policy - open-access
Related In: Results  -  Collection

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fig5: Elevated levels of anti-flagellin IgG are reduced during ART. Plasma levels (OD) of anti-flagellin IgG (a), ratio anti-flagellin IgG/total IgG (b), and total IgG (c) in healthy controls, HIV-1-infected individuals before (= naïve) and after two years of ART (antiretroviral therapy). The plasma samples were diluted 1:1000. The data are presented as median 25–75 interquartile range and total range. P values refer to intergroup differences.
Mentions: Furthermore, we used the anti-flagellin ELISA to evaluate the levels of flagellin IgG in plasma of HIV-1-infected patients before and after two years of ART. At baseline significantly elevated levels of flagellin antibodies were found in HIV-1-infected patients as compared to controls (P < 0.001) (Figure 5(a)). This difference persisted (P < 0.001) when the flagellin antibodies were adjusted to the total IgG (Figure 5(b)), suggesting that the elevation of flagellin antibodies was not due to hypergammaglobulinemia. Moreover, analysis of antimeasles antibodies in 10 patients with severe immune deficiency (CD4+ T-cell counts ≤ 200) supported that the elevation of the flagellin antibodies was not caused by polyclonal activation Supplementary Table 1 (see supplementary material available online at doi:10.1155/2012/263836). The levels of flagellin IgG, total IgG, and the ratio flagellin IgG/total IgG were significantly reduced after two years of ART for the whole group (P < 0.001, P = 0.03, and P < 0.001, resp. Figures 5(a)–5(c)). Additionally a significant reduction of flagellin IgG levels was observed also when the patients were subdivided into those with successful ART and the nonresponders who had remaining low levels of viral replication two years after initiating the ART (P = 0.009; P = 0.001, resp.). The total IgG levels after ART did not decrease in nonresponders as they did in successfully treated patients (P < 0.001) (data not shown).

Bottom Line: Moreover, the stimulatory effect of necrotic extract was inhibited by depletion of HMGB1.Elevated levels of anti-flagellin antibodies were present in plasma from HIV-1-infected patients and significantly decreased during 2 years of antiretroviral therapy.Conclusions.

View Article: PubMed Central - PubMed

Affiliation: Department of Infectious Diseases, Institution of Medicine, Karolinska University Hospital and Karolinska Institutet, 14186 Stockholm, Sweden.

ABSTRACT
Objective. We hypothesized that HMGB1 in complex with bacterial components, such as flagellin, CpG-ODN, and LPS, promotes HIV-1 replication. Furthermore, we studied the levels of antiflagellin antibodies during HIV-1-infection. Methods. Chronically HIV-1-infected U1 cells were stimulated with necrotic extract/recombinant HMGB1 in complex with TLR ligands or alone. HIV-1 replication was estimated by p24 antigen in culture supernatants 48-72 hours after stimulation. The presence of systemic anti-flagellin IgG was determined in 51 HIV-1-infected patients and 19 controls by immunoblotting or in-house ELISA. Results. Flagellin, LPS, and CpG-ODN induced stronger HIV-1 replication when incubated together with necrotic extract or recombinant HMGB1 than activation by any of the compounds alone. Moreover, the stimulatory effect of necrotic extract was inhibited by depletion of HMGB1. Elevated levels of anti-flagellin antibodies were present in plasma from HIV-1-infected patients and significantly decreased during 2 years of antiretroviral therapy. Conclusions. Our findings implicate a possible role of HGMB1-bacterial complexes, as a consequence of microbial translocation and cell necrosis, for immune activation in HIV-1 pathogenesis. We propose that flagellin is an important microbial product, that modulates viral replication and induces adaptive immune responses in vivo.

No MeSH data available.


Related in: MedlinePlus