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• W2330209098 abstract "We thank Nicoli et al.[1] for their thoughtful comments. The B-lymphocyte-induced maturation protein 1 (blimp-1), a zink finger-containing transcriptional repressor coded by the PR domain zinc finger protein 1 (PRDM1) gene, has long been recognized as a master regulator for B-cell development, and has additionally been recognized as an important rheostat, balancing effector function and T-cell exhaustion [2–4]. Recently, several studies of the role of blimp-1 in different cellular subsets in HIV-1 have been published in AIDS[1,5–7] and elsewhere [8,9], as summarized in Table 1. In this edition of AIDS, Nicoli et al.[1] nicely sum up the recent literature and hypothesize that blimp-1 expression may be modulated and/or used to monitor HIV-1 disease progression, as well as response to HIV-1 therapy. Indeed, manipulation of blimp-1 might be a worthwhile target and might help us to answer some important questions in HIV-1 immunology. However, as described by Nicoli et al.[1], the data reported so far are fairly complex. Like the blind men examining the elephant, each of these studies emphasizes a different aspect of blimp-1 biology in HIV-1 [1,5–7]. As Nicoli et al.[1] point out, depending on the study (each of them has merits), the results are – at first sight – partially contradictory and it is not quite clear whether up-regulation of blimp-1 is only beneficiary. Although it would be satisfying to focus on easy stories, the immune system rarely acts in ‘a predictable and clean way’ [2]. Indeed, blimp-1 ‘marches to the beat of its own drum’ [2].Table 1: Summary of published articles about blimp-1 in viral infections.For a fair assessment of the role(s) of blimp-1 in HIV-1, we have to keep in mind that the studies on blimp-1 in HIV-1 were conducted with different methodologies, studying different cells and cohorts. Furthermore, we should also differentiate the complex role of blimp-1 in B-cell and T-cell differentiation, and T-cell exhaustion in acute versus chronic infection; the putative role of blimp-1 for latency and as a HIV-1 restriction factor; and the direct cellular interaction of HIV-1 proteins leading to a changed expression of blimp-1 [6,7,10,11]. So, before we can even think of manipulating blimp-1 in HIV-1, we should step back and study the role of blimp-1 in more detail. What would be the next experiments on a hypothetical HIV-1 immunologist's ‘laundry list’? All studies mentioned above [5–8] would benefit from larger and more stringently defined HIV-1 cohorts (e.g. defining elite controllers as patients with undetectable viral load <50 copies/μl) and longitudinal analysis of patients. Whereas Seddiki et al.[8] show a correlation of blimp-1 expression in CD4+ T cells with immune exhaustion, which nicely fits into the picture, no direct relationship with HIV-1 viral load or CD4+ T-cell counts or other measures of HIV-1 outcome could been shown. Ideally, using major histocompatibility complex class II tetramers [12], it will be interesting to compare virus-specific CD4+ T cells (e.g. HIV-1 versus cytomegalovirus). Also, more information is needed of the role of blimp-1, in particular, in CD4+ T-cell subpopulations like T-follicular helper cells (an important HIV-1 reservoir with possibly low blimp-1 expression) [13] or Tregs (that seem to need blimp-1 to fully function) [14] in HIV-1-infected patients. Surprisingly, there has been no ex-vivo study on blimp-1 expression and function in virus-specific CD8+ T cells in HIV-1 infection so far. The results of the study by Sforza et al.[7] are also exciting, but any effect of TAT protein or other HIV-1 proteins on blimp-1 expression has also to be proven yet in an in-vitro setting. Beisel et al.[5] show preliminary data about an inverse relationship between blimp-1 expression in B cells with HIV-1 progression; however, no formal correlation with B-cell dysregulation, hypergammaglobulinemia and HIV-1-specific humoral responses has been established, and the down-regulation might be circumstantial and due to missing CD4+ T-cell help or lower levels of IL-21 [15]. Lastly, we should try to experimentally study the causative effect of up-regulating /silencing blimp-1 in CD4+ T cells, in order to elucidate whether high blimp-1 expression directly leads to a limitation of the HIV-1 reservoir and, if this is the case, by which mechanism [6]. For this aim, the recently described HIV-1 humanized mouse models will be of great help [16]. At the end of all this work (and only then), we might indeed come to the conclusion that blimp-1 has a dual effect as proposed by Nicoli et al.[1,17]. It might be beneficiary to limit blimp-1 expression during acute infection to decrease immune activation and exhaustion, while induction of blimp-1 might help to purge the HIV-1 reservoir [6]. Acknowledgements We thank Nabila Seddiki for thoughtful discussions. J.S.zW. was funded by the DFG (SFB841, A6). J.S.zW. and C.B. are funded by the DZIF. Conflicts of interest There are no conflicts of interest." @default.
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• W2330209098 title "The elephant and the blind men" @default.
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