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Concerted effect of lymphopenia, viraemia and T-cell activation on Fas expression of peripheral B cells in HIV-1-infected patients

Rethi, Bencea,*; Sammicheli, Stefanoa,d,*; Amu, Sylviea; Pensieroso, Simonea,e; Hejdeman, Bob; Schepis, Danikac; Thang, Pham H.a; Chiodi, Francescaa

doi: 10.1097/QAD.0b013e32835b8c5e
Basic Science

Objective: Decreased memory B-cell maintenance during HIV-1 infection has been associated with the viraemia-induced accumulation of activated memory B cells, sensitive to Fas-mediated apoptosis. We aimed at clarifying whether other B-cell subsets might also be affected by an increased Fas expression in HIV-1-infected patients, and we studied the possible contribution of viraemia, lymphopenia or T-cell activation in Fas upregulation on B cells. We analysed whether Fas upregulation might have collaborative effects with the dysregulation of other B-cell modulatory molecules, leukocyte-associated immunoglobulin-like receptor 1 (LAIR1) and programmed cell death protein 1 (PD-1), on B-cell homeostasis.

Design: Fas, LAIR1 and PD-1 were analysed on B-cell subpopulations in HIV-1-infected patients who were treatment naive, nonlymphopenic; antiretroviral therapy (ART)-treated, nonlymphopenic; or ART-treated, lymphopenic or in noninfected controls.

Methods: Flow cytometry was used to study B-cell subsets and Milliplex for serum cytokines.

Results: Fas expression increased on all B-cell subpopulations of viraemic or lymphopenic individuals. The decreased ratio of resting memory B cells and their increased Fas expression were not normalized by ART. Cytokines associated with T-cell activation might influence Fas expression on the naive and transitional B cells. LAIR1 expression decreased in all HIV-1-infected patients, but only on memory B cells, whereas PD-1 increased on resting memory B cells in viraemic patients.

Conclusion: Fas is regulated by the concerted action of viraemia, lymphopenia and T-cell activation during HIV-1 infection, and Fas expression is altered on all peripheral B-cell subsets. Resting memory B-cell homeostasis shows the highest sensitivity to HIV-1-induced perturbations.

aDepartment of Microbiology, Tumor and Cell Biology, Karolinska Institutet

bVenhälsan, South Hospital

cDepartment of Medicine, Unit of Rheumatology, Karolinska Institutet, Stockholm, Sweden

dDynamics of Immune Responses, Division of Immunology

eViral Evolution and Transmission Unit, San Raffaele Scientific Institute, Milan, Italy.

*Bence Rethi and Stefano Sammicheli contributed equally to the writing of this article.

Correspondence to Bence Rethi, MTC, Karolinska Institutet, Stockholm 17177, Nobles väg 16, Sweden. Tel: +46852486777; fax: +468330498; e-mail: Bence.Rethi@ki.se

Received 6 June, 2012

Revised 4 October, 2012

Accepted 16 October, 2012

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© 2013 Lippincott Williams & Wilkins, Inc.