Acute depletion of activated memory B cells involves the PD-1 pathway in rapidly progressing SIV-infected macaques

• Type of Material: Article
• Authors: Kehmia Titanji, Emory University; Lakshmi Chennareddi, Emory University; Matam Vijay-Kumar, Emory University; Andrew T Gewirtz, Emory University; Gordon J. Freeman, Emory University; Rama Rao Amara, Emory University; Vijayakumar Velu, Emory University
• Language: English
• Date: 2010-11-01
• Publisher: American Society for Clinical Investigation
• Publication Version: Final Published Version
• Copyright Statement: © 2010, American Society for Clinical Investigation
• Final Published Version (URL): http://www.jci.org/articles/view/43271
• Title of Journal or Parent Work: Journal of Clinical Investigation
• ISSN: 0021-9738
• Volume: 120
• Issue: 11
• Start Page: 3878
• End Page: 3890
• Grant/Funding Information: This work was supported by NIH/National Institute of Allergy and Infectious Diseases grants R01 AI057029, R01 AI074471, and R01 AI071852 to R.R. Amara; Yerkes National Primate Research Center base grant P51 RR00165; and Emory CFAR grants P30 AI050409, R01 AI074417, and P01 AI08080192 to G.J. Freeman.
• Research Categories: Health Sciences, Medicine and Surgery; Psychology, Clinical

Abstract

Rapid progression to AIDS is a significant problem, especially in developing countries, where the majority of HIV-infected individuals reside. As rapid disease progression is also frequently observed in SIV-infected macaques, they represent a valuable tool to investigate the pathogenesis of this condition in humans. Here, we have shown that pathogenic SIV infection in rhesus macaques resulted in a rapid depletion (as early as week 2) of activated memory B (CD21–CD27+; mBAct) cells that was strongly associated with rapid disease progression. This depletion was progressive and sustained in rapid progressors, but less severe and transient in typical progressors. Because of the rapid and sustained depletion of mBAct cells, rapid progressors failed to develop SIV-specific Ab responses, showed a decline in non–SIV-specific Ab titers, and succumbed faster to intestinal bacterial infections. Depletion of mBAct cells was strongly associated with preferential depletion of mBAct cells expressing programmed death-1 (PD-1), and in vitro blockade of PD-1 improved their survival. Furthermore, in vivo PD-1 blockade in SIV-infected macaques enhanced Ab responses to non-SIV as well as SIV Ags. Our results identify depletion of mBAct cells as a very early predictor of rapid disease progression in pathogenic SIV infection and suggest an important role for the PD-1 pathway in depletion of mBAct cells and impaired humoral immune responses in SIV-infected macaques.