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Decoupling activation and exhaustion of B cells in spontaneous controllers of HIV infection

Sciaranghella, Gaia; Tong, Neath; Mahan, Alison E.; Suscovich, Todd J.; Alter, Galit

doi: 10.1097/QAD.0b013e32835bd1f0
Basic Science: Concise Communication

Objective: To define the impact of chronic viremia and associated immune activation on B-cell exhaustion in HIV infection.

Design: Progressive HIV infection is marked by B-cell anergy and exhaustion coupled with dramatic hypergammaglobulinemia. Although both upregulation of CD95 and loss of CD21 have been used as markers of infection-associated B-cell dysfunction, little is known regarding the specific profiles of dysfunctional B cells and whether persistent viral replication and its associated immune activation play a central role in driving B-cell dysfunction.

Methods: Multiparameter flow cytometry was used to define the profile of dysfunctional B cells. The changes in the expression of CD21 and CD95 were tracked on B-cell subpopulations in patients with differential control of viral replication.

Results: Although the emergence of exhausted, CD21low tissue-like memory B cells followed similar patterns in both progressors and controllers, the frequency of CD21low activated memory B cells was lower in spontaneous controllers.

Conclusion: Our results suggest that the loss of CD21 and the upregulation of CD95 occur as separate events during the development of B-cell dysfunction. The loss of CD21 is a marker of B-cell exhaustion induced in the absence of appreciable viral replication, whereas the upregulation of CD95 is tightly linked to persistent viral replication and its associated immune activation. Thus, these dysfunctional profiles potentially represent two functionally distinct states within the B-cell compartment.

Ragon Institute of MGH, MIT and Harvard, Boston, Massachusetts, USA.

Correspondence to Dr Galit Alter, Ragon Institute of MGH, MIT and Harvard, 149 13th Street, Charlestown, MA 02129, USA. Tel: +1 617 724 0546; fax: +1 617 726 5411; e-mail:

Received 24 May, 2012

Revised 12 October, 2012

Accepted 23 October, 2012

© 2013 Lippincott Williams & Wilkins, Inc.