期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 120, 期 11, 页码 3878-3890出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI43271
关键词
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资金
- NIH/National Institute of Allergy and Infectious Diseases [R01 AI057029, R01 AI074471, R01 AI071852]
- Yerkes National Primate Research Center [P51 RR00165]
- Emory CFAR [P30 AI050409, R01 AI074417, P01 AI08080192]
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 Sly infection in rhesus macaques resulted in a rapid depletion (as early as week 2) of activated memory B (CD21(-)CD27(+); mB(Act)) 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 mB(Act) 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 mB(Act) 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 mB(Act) cells as a very early predictor of rapid disease progression in pathogenic SW 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.
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