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Aspects of immune activation in HIV-1 infection

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posted on 2024-09-02, 23:09 authored by Piotr Nowak

Abnormal immune system activation is central in HIV-1 pathogenesis leading to CD4+ T-cell depletion and inappropriate immune responses. Disease stage and HIV load strongly correlate with the immune activation level which decreases under antiretroviral therapy (ART).

The general aim was to investigate the role exerted by immune activation in HIV-1 infection and to characterise the contribution of high mobility group box protein 1 (HMGB1). This was fulfilled by: (a) studying two unique cohorts consisting of four orthotopic liver transplant (OLT) patients receiving ART and immunosuppressive therapy, and 22 patients with early primary HIV infection (PHI) who underwent both ART and analytical treatment interruption (ATI); (b) characterising the interaction between HMGB1 and HIV-1 in vitro and in vivo.

HIV-1 was controlled by ART, without any major contribution of the adaptive immunity, as shown by low or undetectable viral load (VL) and restricted viral diversity-divergence, in the four OLT patients. Also, the kinectics of VL during PHI in an OLT subject suggested that the initial rapid viral decline is caused by the innate immunity or reduced immune activation. Furthermore, the lower degree of immune activation in 22 PHI-patients was associated with lower viral replication and improved long-term virological outcome, as implied by the kinetics of 13 cytokines and chemokines during PHI and post ATI. We showed that PHI is indeed associated with generalized immune activation not restricted to a specific cytokine/chemokine pattern.

HMGB1 is an abundant protein with intracellular localisation and function exerting DNA flexibilisation and regulation of transcription. Additionally, this protein can be released actively after activation of macrophages, and dendritic cells, and passively by necrotic cells. Exogenous HMGB1 is a proinflammatory mediator that has been attributed a plethora of functions. Our data indicate that HMGB1 has an important role during HIV-1 pathogenesis. Thus, intracellular HMGB1 could inhibit the LTR mediated HIV-1 transcription in epithelial and monocytic cells. The physiological overexpression of HMGB1 in myeloid cells might be responsible for the restricted HIV-1 replication in these cells. Moreover, extracellular HMGB1 had a regulatory function on HIV-1 replication, tested in two models, latent and acute. We found upregulation of viral replication after HMGB1 stimulation of U1 cells and downregulation in acutely infected primary macrophages. The latter effect could be explained by â-chemokines (MIP-1á, MIP-1â, RANTES) release from these cells after HMGB1 induction. ELISA analysis revealed that the plasma levels of HMGB1 are significantly elevated in HIV-1 infected individuals (n=43) as compared to HIV-1 negative individuals (n=14). Additionally, the HIV-1 infected patients with clinical complications (n=16) had higher levels of HMGB1 than asymptomatic patients with preserved (n=14) or deteriorated immune system (n=13).

In conclusion, the data included in this thesis stress the essential role of immune activation in HIV-1 pathogenesis and place HMGB1 as an important factor that can modify the HIV-1 replication and contribute to the dysregulation of the immune system.

List of scientific papers

I. Nowak P, Schvarcz R, Ericzon BG, Flamholc L, Sonnerborg A. (2003). Follow-up of antiretroviral treatment in liver transplant recipients with primary and chronic HIV type 1 infection. AIDS Res Hum Retroviruses. 19(1): 13-19
https://pubmed.ncbi.nlm.nih.gov/12581512

II. Naghavi MH, Nowak P, Andersson J, Sonnerborg A, Yang H, Tracey KJ, Vahlne A. (2003). Intracellular high mobility group B1 protein (HMGB1) represses HIV-1 LTR-directed transcription in a promoter- and cell-specific manner. Virology. 314(1): 179-89
https://pubmed.ncbi.nlm.nih.gov/14517071

III. Nowak P, Barqasho B, Treutiger CJ, Harris HE, Tracey KJ, Andersson J, Sonnerborg A. (2006). HMGB1 activates replication of latent HIV-1 in a monocytic cell-line, but inhibits HIV-1 replication in primary macrophages. Cytokine. 34(1-2): 17-23
https://pubmed.ncbi.nlm.nih.gov/16697213

IV. Barqasho B, Nowak P, Tjernlund A, Kinloch S, Goh L-E, Lampe F, Fisher M, Andersson J, Sönnerborg A. (2007). Kinetics of plasma cytokines and chemokines during primary HIV-1 infection and after analytical treatment interruption. [Submitted]

V. Nowak P, Barqasho B, Sonnerborg A. (2007). Elevated plasma levels of high mobility group box protein 1 in patients with HIV-1 infection. AIDS. 21(7): 869-71
https://pubmed.ncbi.nlm.nih.gov/17415043

History

Defence date

2007-06-15

Department

  • Department of Laboratory Medicine

Publication year

2007

Thesis type

  • Doctoral thesis

ISBN

978-91-7357-190-6

Number of supporting papers

5

Language

  • eng

Original publication date

2007-05-25

Author name in thesis

Nowak, Piotr

Original department name

Department of Laboratory Medicine

Place of publication

Stockholm

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