This appears to be directly attributable to viral infection of the CD4+ T cells since the induction of Blimp-1 is diminished when this is prevented [22]. A prior study showing that HIV infection activates the unfolded protein response [23], which has been independently observed to induce Blimp-1 [24], may provide an explanation for this phenomenon. Other recent work has highlighted the fact that

in murine CD8+ T cells, cell–cell contact induced ligation of the inhibitory receptor CTLA-4, leading to activation of the Hippo pathway, which induced Ulixertinib Blimp-1 expression [25]. Although this work focused on CD8+ T cells, CTLA-4 is a receptor that’s expression is lower in the CD4+ T cells of LTNPs compared with individuals with CHI [26] and CTLA-4 induction of Blimp-1 is, therefore, potentially another reason for the elevated Blimp-1 seen in those with CHI (Fig. 1). The paper by Siddiki et al. [18] in this issue of EJI, therefore, provides firm evidence

that the observations of the importance of Blimp-1 Navitoclax expression in the immune exhaustion seen in chronic murine LCMV have relevance to human HIV infection. But does this apply equally to mice and men? We cannot be certain of the applicability of murine LCMV research on T-cell differentiation to the human system. LCMV infection induces a response in which at least 50% of the entire CD8+ T-cell pool becomes Ag-specific [27]; while the model may ultimately be predictive of HIV during the phase of high viral load, no human PR-171 cost infection reaches this level of response. The authors’ observation of parity between

the two systems (mouse LCMV and human HIV) is not only important but also has further implications for our understanding of Blimp-1. In chronic LCMV, Blimp-1 haploid-insufficient T cells are better able to control chronic infection than either fully deficient or WT T cells [15]. The implication of this is that it is not simply the avoidance of Blimp-1 expression, and thereby exhaustion, which leads to better viral control but rather that a certain level of expression of Blimp-1 is necessary for viral control. In keeping with Blimp-1′s role in terminal T-cell differentiation, Blimp-1-deficient T cells have been demonstrated to have diminished cytolytic effector function [13]. Thus too much Blimp-1 promotes exhaustion while too little prevents full effector function, in either situation viral control is diminished. The improved ability of LTNPs to control HIV infection may not entirely relate to avoidance of Blimp-1 expression but may instead relate more specifically to achieving the optimum level of Blimp-1 expression. With this, we can see the interest of the study by Seddiki et al.

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