Elevated plasma levels of high mobility group box protein 1 in patients with HIV-1 infection
Nowak, Piotra; Barqasho, Babiloniaa; Sönnerborg, Andersa,b
aDivisions of Clinical Virology, Sweden
bInfectious Diseases, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
Received 20 November, 2006
Revised 11 December, 2006
Accepted 19 December, 2006
High mobility group box protein 1 (HMGB1) is a potent proinflammatory mediator. It has a dichotomic effect on HIV-1 replication in vitro but its role in vivo is unknown. Here we report the novel finding that plasma HMGB1 levels are elevated in HIV-1-infected patients, with the highest concentrations in patients with clinical complications. HMGB1 is likely to contribute to immunoactivation in HIV-1 infection in vivo.
High mobility group box protein 1 (HMGB1) is an intracellular protein that is released into the extracellular environment in both an active and a passive manner . It functions as a critical mediator of systemic inflammation and immunoactivation. Enhanced HMGB1 levels correlating with the clinical outcome have been reported in a variety of conditions with acute and chronic inflammation . Immunoactivation is a central part of the HIV-1 pathogenesis contributing to CD4 T-cell depletion and to inappropriate immune responses to pathogens . The disease stage and viral load strongly correlate with immunoactivation levels . Furthermore, an important benefit of interventions with antiretroviral therapy (ART) is decreased immunoactivation [5,6]. We have previously reported that overexpression of HMGB1 intracellularly repressed HIV-1 gene expression in HeLa cells and could be responsible for the slow mode of HIV-1 replication in monocytes/macrophages . In addition, extracellular HMGB1 was shown to have a dual mode of action on HIV-1 replication; upregulating it in chronically infected monocytic cell-lines and suppressing it in primary infected macrophages . The latter effect could be explained by the induction of β-chemokine production (macrophage inflammatory proteins 1α and 1β, and regulated upon activation: normal T-cell expressed/secreted) by HMGB1 stimulation. Our earlier experimental data thus suggest that HMGB1 may play an important role in the immunoactivation and regulation of HIV-1 replication in macrophages.
In this study, we measured levels of HMGB1 in plasma from 14 healthy HIV-1-negative volunteers and 43 treatment-naive HIV-1-infected individuals. Three patient categories were defined: group A (n = 14): those with preserved immune status (> 600 CD4 T cells/μl; median 950, range 655–1519) and a low viral load (median 350 copies/ml, range 19–1900); group B (n = 13): those with deteriorated immune status (< 400 CD4 T cells/μl; median 246, range 58–374) and a high viral load (347 000 copies/ml, range 20 000–106); group C (n = 16): those with deteriorated immune status (≤ 300 CD4 T cells/μl; median 85, range 8–300), a high viral load (541 000 copies/ml, range 8900–106) and opportunistic conditions  at the time of sampling. Opportunistic conditions included tuberculosis (pulmonary, lymph node, disseminated), pneumonia (bacterial, Pneumocystis jiroveci), candidiasis (oropharyngeal, oesophagal), toxoplasmosis, aspergillosis, neurosyfilis, B-cell lymphoma and Mycobacterium avium complex infection. Ethical approval (43/02) was obtained from the Ethical Committee at Karolinska Institutet. Plasma HIV-1 RNA and peripheral blood CD4 and CD8 T cell counts were quantified by routine methods. The plasma HMGB1 levels were determined using an enzyme-linked immunosorbent assay following the manufacturer's protocol (Shino-Test Corporation, Japan) [10–12]. Statistical analyses were performed using the Mann–Whitney and Spearman rank tests.
We found higher plasma levels of HMGB1 (median 5.3 ng/ml, range 0.5–87.5) in HIV-1-infected patients, compared with HIV-negative healthy controls (median 1.4 ng/ml, range 0.0–4.4, P < 0.001; Fig. 1a). HIV-1-infected patients with opportunistic conditions had higher HMGB1 levels (median 8.4 ng/ml, range 1.1–71.8) compared with asymptomatic patients with preserved (median 4.7 ng/ml, range 1.7–87.5, P < 0.05) or deteriorated immune (median 3.8 ng/ml, range 0.5–83.4, P < 0.05) systems (Fig. 1b). There was no significant difference in HMGB1 levels between the two latter groups. No difference was observed in HMGB1 levels within the symptomatic patients with regard to specific opportunistic conditions. All categories of HIV-1-infected patients had increased plasma HMGB1 levels when compared with HIV-1-negative controls (groups A and C: P < 0.001; group B: P < 0.01). In addition, no statistically significant correlation was found between the plasma HMGB1 levels and sex, age, viral load, CD4 or CD8 T-cell counts, respectively (data not shown).
Our results show that HMGB1 can be detected in the circulation of chronically infected HIV-1 individuals, with the highest concentrations in patients with clinical complications. Using a similar technique, the levels were comparable to those in patients with disseminated intravascular coagulation or with acute pancreatitis [12,13]. The source of HMGB1 in the plasma of HIV-1-infected patients has not yet been elucidated. Two mechanisms can be assumed. HMGB1 can be released from monocytes, macrophages, dendritic and endothelial cells as a result of cytokine or endotoxin stimulation . Also, passive release occurs during necrosis, but not during apoptosis when HMGB1 remains in the nuclei, tightly bound to chromatin . Immunoactivation and cell death are hallmarks of HIV-1 pathogenesis, although the relative impact of apoptosis and necrosis, respectively, is still an issue of debate .
The data could support the view that a profound activation of the immune system is related to high HMGB1 levels. In addition, the cytopathic effects of HIV-1 may contribute to the enhanced HMGB1 levels . Unpublished data from our laboratory (P. Nowak et al., in preparation) reveal that HIV-1 infection of T-cell lines results in cytopathic effects and subsequent HMGB1 release during necrosis. This is further supported by the finding of extracellular HMGB1 release in vitro after cytopathic West Nile virus infection .
The excessive immunoactivation found in HIV-1 infection is reduced during successful ART [3,5,6]. Therefore, therapeutic interference with anti-HMGB1 monoclonal antibodies as well as active HMGB1 release inhibitors (ethyl puryvate, stearoyl lysophosphatidylcholine), which have been used successfully in animal models of sepsis and arthritis , may not add substantial improvements to the long-term clinical outcome of ART. More studies of HGMB1 in HIV-1-infected patients may, however, give important information about the role of this protein in important aspects of immunoactivation and regulation of HIV-1 replication during HIV-1 pathogenesis.
Sponsorship: This study was supported by the Swedish Medical Research Council, SIDA/SAREC, and Swedish Physicians Against AIDS Foundation.
1. Lotze MT, Tracey KJ. High-mobility group box 1 protein (HMGB1): nuclear weapon in the immune arsenal. Nat Rev Immunol 2005; 5:331–342.
2. Ulloa L, Messmer D. High-mobility group box 1 (HMGB1) protein: friend and foe. Cytokine Growth Factor Rev 2006; 17:189–201.
3. Appay V, Boutboul F, Autran B. The HIV infection and immune activation: “to fight and burn”. Curr Infect Dis Rep 2005; 7:473–479.
4. Hazenberg MD, Otto SA, van Benthem BH, Roos MT, Coutinho RA, Lange JM, et al
. Persistent immune activation in HIV-1 infection is associated with progression to AIDS. AIDS 2003; 17:1881–1888.
5. Autran B, Carcelain G, Li TS, Blanc C, Mathez D, Tubiana R, et al
. Positive effects of combined antiretroviral therapy on CD4+ T cell homeostasis and function in advanced HIV disease. Science 1997; 277:112–116.
6. Aleman S, Pehrson P, Sonnerborg A. Kinetics of beta-chemokine levels during anti-HIV therapy. Antivir Ther 1999; 4:109–115.
7. Naghavi MH, Nowak P, Andersson J, Sonnerborg A, Yang H, Tracey KJ, Vahlne A. Intracellular high mobility group B1 protein (HMGB1) represses HIV-1 LTR-directed transcription in a promoter- and cell-specific manner. Virology 2003; 314:179–189.
8. Nowak P, Barqasho B, Treutiger CJ, Harris HE, Tracey KJ, Andersson J, Sonnerborg A. HMGB1 activates replication of latent HIV-1 in a monocytic cell-line, but inhibits HIV-1 replication in primary macrophages. Cytokine 2006; 34:17–23.
9. Benson CA, Kaplan JE, Masur H, Pau A, Holmes KK. Treating opportunistic infections among HIV-exposed and infected children: recommendations from CDC, the National Institutes of Health, and the Infectious Diseases Society of America. MMWR Recomm Rep 2004; 53:1–112.
10. Yamada S, Yakabe K, Ishii J, Imaizumi H, Maruyama I. New high mobility group box 1 assay system. Clin Chim Acta 2006; 372:173–178.
11. Tagami K, Yujiri T, Tanimura A, Mitani N, Nakamura Y, Ariyoshi K, et al
. Elevation of serum high-mobility group box 1 protein during granulocyte colony-stimulating factor-induced peripheral blood stem cell mobilisation. Br J Haematol 2006; 135:567–569.
12. Yasuda T, Ueda T, Takeyama Y, Shinzeki M, Sawa H, Nakajima T, et al
. Significant increase of serum high-mobility group box chromosomal protein 1 levels in patients with severe acute pancreatitis. Pancreas 2006; 33:359–363.
13. Hatada T, Wada H, Nobori T, Okabayashi K, Maruyama K, Abe Y, et al
. Plasma concentrations and importance of high mobility group box protein in the prognosis of organ failure in patients with disseminated intravascular coagulation. Thromb Haemost 2005; 94:975–979.
14. Scaffidi P, Misteli T, Bianchi ME. Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature 2002; 418:191–195.
15. Plymale DR, Tang DS, Comardelle AM, Fermin CD, Lewis DE, Garry RF. Both necrosis and apoptosis contribute to HIV-1-induced killing of CD4 cells. AIDS 1999; 13:1827–1839.
16. Wang H, Ward MF, Fan XG, Sama AE, Li W. Potential role of high mobility group box 1 in viral infectious diseases. Viral Immunol 2006; 19:3–9.
17. Chu JJ, Ng ML. The mechanism of cell death during West Nile virus infection is dependent on initial infectious dose. J Gen Virol 2003; 84:3305–3314.
18. Mantell LL, Parrish WR, Ulloa L. Hmgb-1 as a therapeutic target for infectious and inflammatory disorders. Shock 2006; 25:4–11.
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© 2007 Lippincott Williams & Wilkins, Inc.
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