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Influence of Plasma Cell Niche Factors on the Recruitment and Maintenance of IRF4hi Plasma Cells and Plasmablasts in Vaccinated, SIV-Infected Rhesus Macaques with Low and High Viremia.

Influence of Plasma Cell Niche Factors on the Recruitment and Maintenance of IRF4hi Plasma Cells and Plasmablasts in Vaccinated, SIV-Infected Rhesus Macaques with Low and High Viremia.
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Shaw JM, Miller-Novak LK, Mohanram V, McKinnon K, Demberg T, Vargas-Inchaustegui DA, Venzon D, Robert-Guroff M,


Shaw JM, Miller-Novak LK, Mohanram V, McKinnon K, Demberg T, Vargas-Inchaustegui DA, Venzon D, Robert-Guroff M, (click to view)

Shaw JM, Miller-Novak LK, Mohanram V, McKinnon K, Demberg T, Vargas-Inchaustegui DA, Venzon D, Robert-Guroff M,

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Journal of virology 2016 12 07() pii

Abstract

In a recent study, we found protection following SIV exposure correlated with rectal plasma cell frequency in vaccinated female rhesus macaques. We sought to determine if these same macaques maintained high mucosal plasma cell frequencies post-infection and if this translated to reduced viremia. Although delayed SIV acquisition did not predict subsequent viral control, alterations existed in the distribution of plasma cells and plasmablasts between macaques that exhibited high or low viremia. Flow cytometric analysis of cells from rectal biopsies, bone marrow, and mesenteric lymph nodes of vaccinated infected, unvaccinated infected, and uninfected macaques identified two main IRF4(hi) subsets of interest: CD138+ plasma cells, and CD138- plasmablasts. In rectal tissue, plasma cell frequency positively correlated with plasma viremia and unvaccinated macaques had increased plasma cells and plasmablasts compared to vaccinated animals. Likewise, plasmablast frequency in the mesenteric lymph node correlated with viremia. However in bone marrow, plasmablast frequency negatively correlated with viremia. Accordingly, low viremic macaques had a higher frequency of both bone marrow IRF4(hi) subsets compared to animals with high viremia. Significant reciprocal relationships between rectal and bone marrow plasmablasts suggested efficient trafficking to the bone marrow as opposed to the rectal mucosa was linked to viral control. mRNA expression analysis of proteins involved in establishment of plasma cell niches in sorted bone marrow and rectal cell populations further supported this model and offered a window into differential mRNA expression patterns in these tissues.

IMPORTANCE
As key antibody producers, plasma cells and plasmablasts are critical components of vaccine-induced immunity to HIV-1 in humans and SIV in the macaque model; however few have attempted to examine the role of these cells in viral suppression post-infection. Our results suggest plasmablast trafficking to and retention in the bone marrow plays a previously unappreciated role in viral control and contrasts the potential contribution of mucosal plasma cells to mediate protection at sites of infection with that of bone marrow plasmablasts and plasma cells to viral control during chronic infection. Manipulation of niche factors influencing the distribution and maintenance of these critical antibody-secreting cells may serve as potential therapeutic targets to enhance anti-viral responses post-vaccination and post-infection.

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