Blimp-1, an Intrinsic Factor that Represses HIV-1 Proviral Transcription in Memory CD4+ T Cells

Abstract

CD4+ T cell subsets differentially support HIV-1 replication. For example, quiescent CD4+ memory T cells are susceptible to HIV-1 infection but do not support robust HIV-1 transcription and have been implicated as the primary reservoir of latent HIV-1. T cell transcription factors that regulate maturation potentially limit HIV-1 transcription and mediate the establishment and maintenance of HIV-1 latency. We report that B lymphocyte-induced maturation protein-1 (Blimp-1), a critical regulator of B and T cell differentiation, is highly expressed in memory CD4+ T cells compared to naïve CD4+ T cells and represses basal and Tat-mediated HIV-1 transcription. Blimp-1 binds an interferon-stimulated response element (ISRE) within HIV-1 provirus and it is displaced following T cell activation. Reduction of Blimp-1 in infected primary T cells including CD4+ memory T cells increases RNA polymerase II processivity, histone acetylation and baseline HIV-1 transcription. Therefore, the transcriptional repressor, Blimp-1, is an intrinsic factor that predisposes CD4+ memory T cells to latent HIV-1 infection.

Physiological and Pathological Transcriptional Activation of Endogenous Retroelements Assessed by RNA-Sequencing of B Lymphocytes

“…Indeed, this relatively high affinity of ERV LTRs for host transcription factors seems to be an intrinsic, evolutionarily shared property ( Dunn et al, 2005 ), and underlies their ability to establish and rewire host gene regulatory networks ( Rebollo et al, 2012 ). Whether BCL6 or Blimp-1 directly affect transcription of ERVs is not currently known, but Blimp-1 has been reported to repress expression of HIV-1 proviruses in T cells ( Kaczmarek Michaels et al, 2015 ). Therefore, BCL6 may induce expression of ERVs indirectly, through its established role in repressing the repressor Blimp-1 ( Crotty et al, 2010 ).…”

RNAP II processivity is a limiting step for HIV-1 transcription independent of orientation to and activity of endogenous neighboring promoters

“…Therefore, HIV-1 transcription is not necessarily incompatible with an active upstream endogenous promoter. More importantly, although it is unclear as to whether common pathways are responsible for initially repressing HIV-1 transcription, there is a convergence of repressive mechanisms on RNAP II processivity suggesting that this is a common limiting step that maintains HIV-1 latency in multiple cellular contexts including primary cells (Kaczmarek Michaels et al, 2015; Natarajan et al, 2013). Exploring agents that modulate RNAP II processiveness will potentially identify novel therapeutics against latently infected cells.…”

Clonal CD4+ T cells in the HIV-1 latent reservoir display a distinct gene profile upon reactivation

“…How does a subset of latent cells divide and still survive despite expression of HIV-1? Our single cell transcriptomic analysis of purified primary CD4+ T cells demonstrates that reactivated latent cells can express a distinct transcriptional program that includes muted responses to type I interferon and factors such as MiR-155 and PRDM1 that can suppress HIV-1 transcription 28 , 31 , 32 . We speculate that active HIV-1 suppression during CD4+ T cell division could be one of the mechanisms that maintains the latent reservoir.…”

“…Finally, a number of transcription factors were among the top 15 differentially expressed genes, including the top differentially expressed gene, PRDM1 (1365x). PRDM1 represses HIV-1 proviral transcription in memory CD4+ T cells by inhibition of HIV tat 31 , and its overexpression is associated with lower levels of HIV-1 transcription in elite controllers 32 .…”