The Molecular Biology of HIV Latency

Khoury, Georges; Darcis, Gilles; Lee, Michelle Y.; Bouchat, Sophie; Driessche, Benoît Van; Purcell, Damian F. J.; Lint, Carine Van

doi:10.1007/978-981-13-0484-2_8

Cited by 48 publications

(46 citation statements)

References 102 publications

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“…Most LRAs selected so far to relieve transcriptional blocks act on signaling pathways and histone acetylation [5,64] but are not specific to HIV LTR promoters or targeted to the reservoirs, thus their effect should be considered globally on genes and cellular machineries of cell populations [48][49][50]65]. The LRA-induced changes in cellular peptidase activities took 48 aCD3/CD28 at 24, 48 and 72h post-infection at a 4:1 CTL:CD4 ratio.…”

Section: Discussionmentioning

confidence: 99%

Latency reversal agents modulate HIV antigen processing and presentation to CD8 T cells

et al. 2020

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Latency reversal agents (LRA) variably induce HIV re-expression in CD4 T cells but reservoirs are not cleared. Whether HIV epitope presentation is similar between latency reversal and initial infection of CD4 T cells is unknown yet crucial to define immune responses able to detect HIV-infected CD4 T cells after latency reversal. HIV peptides displayed by MHC comes from the intracellular degradation of proteins by proteasomes and post-proteasomal peptidases but the impact of LRAs on antigen processing is not known. Here we show that HDAC inhibitors (HDCAi) reduced cytosolic proteolytic activities while PKC agonists (PKCa) increased them to a lesser extent than that induced by TCR activation. During the cytosolic degradation of long HIV peptides in LRA-treated CD4 T cells extracts, HDACi and PKCa modulated degradation patterns of peptides and altered the production of HIV epitopes in often opposite ways. Beyond known HIV epitopes, HDACi narrowed the coverage of HIV antigenic fragments by 8-11aa degradation peptides while PKCa broadened it. LRAs altered HIV infection kinetics and modulated CD8 T cell activation in an epitope-and time-dependent manner. Interestingly the efficiency of endogenous epitope processing and presentation to CD8 T cells was increased by PKCa Ingenol at early time points despite low levels of antigens. LRA-induced modulations of antigen processing should be considered and exploited to enhance and broaden HIV peptide presentation by CD4 T cells and to improve immune recognition after latency reversal. This property of LRAs, if confirmed with other antigens, might be exploited to improve immune detection of diseased cells beyond HIV.

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Section: Discussionmentioning

confidence: 99%

Latency reversal agents modulate HIV antigen processing and presentation to CD8 T cells

et al. 2020

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“…Human immunodeficiency virus type 1 (HIV-1) has been shown to encode a small basic protein known as the transactivator of transcription (Tat) (Rice and Mathews, 1988) and as recently reviewed (Spector et al, 2019). Tat is a multifunctional protein, though it is primarily responsible for recruitment of the host positive transcription elongation factor b (P-TEFb) by interaction with an RNA stem-loop designated the transactivation response (TAR) element, which is encoded by the viral long terminal repeat (LTR) (Dingwall et al, 1989;Li et al, 2011;Khoury et al, 2018). This interaction leads to efficient transactivation of HIV-1 and this function has been shown to be contained within the first exon of Tat (residues 1-58) (Kuppuswamy et al, 1989;Link et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

HIV-1 Tat Length: Comparative and Functional Considerations

et al. 2020

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“…Thus, depletion of UNG2 may contribute to the observed effects of HDACi on both immune-and autoimmune responses. Further, HDACi promote reversal of HIV-1 latency by increasing the LTR activity [5,81], a major obstacle to permanently eradicate infection [82]. Loss of UNG also increase LTR activity [83] and the potential contribution of HDACi-mediated UNG2 depletion in reversal of HIV-1 latency warrants further investigation.…”

Section: Discussionmentioning

confidence: 99%

HDACi mediate UNG2 depletion, dysregulated genomic uracil and altered expression of oncoproteins and tumor suppressors in B- and T-cell lines

et al. 2020

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Background: HDAC inhibitors (HDACi) belong to a new group of chemotherapeutics that are increasingly used in the treatment of lymphocyte-derived malignancies, but their mechanisms of action remain poorly understood. Here we aimed to identify novel protein targets of HDACi in Band T-lymphoma cell lines and to verify selected candidates across several mammalian cell lines. Methods: Jurkat T-and SUDHL5 B-lymphocytes were treated with the HDACi SAHA (vorinostat) prior to SILAC-based quantitative proteome analysis. Selected differentially expressed proteins were verified by targeted mass spectrometry, RT-PCR and western analysis in multiple mammalian cell lines. Genomic uracil was quantified by LC-MS/MS, cell cycle distribution analyzed by flow cytometry and class switch recombination monitored by FACS in murine CH12F3 cells. Results: SAHA treatment resulted in differential expression of 125 and 89 proteins in Jurkat and SUDHL5, respectively, of which 19 were commonly affected. Among these were several oncoproteins and tumor suppressors previously not reported to be affected by HDACi. Several key enzymes determining the cellular dUTP/dTTP ratio were downregulated and in both cell lines we found robust depletion of UNG2, the major glycosylase in genomic uracil sanitation. UNG2 depletion was accompanied by hyperacetylation and mediated by increased proteasomal degradation independent of cell cycle stage. UNG2 degradation appeared to be ubiquitous and was observed across several mammalian cell lines of different origin and with several HDACis. Loss of UNG2 was accompanied by 30-40% increase in genomic uracil in freely cycling HEK cells and reduced immunoglobulin class-switch recombination in murine CH12F3 cells. Conclusion: We describe several oncoproteins and tumor suppressors previously not reported to be affected by HDACi in previous transcriptome analyses, underscoring the importance of proteome analysis to identify cellular effectors of HDACi treatment. The apparently ubiquitous depletion of UNG2 and PCLAF establishes DNA base excision repair and translesion synthesis as novel pathways affected by HDACi treatment. Dysregulated genomic uracil

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The Molecular Biology of HIV Latency

Cited by 48 publications

References 102 publications

Latency reversal agents modulate HIV antigen processing and presentation to CD8 T cells

Latency reversal agents modulate HIV antigen processing and presentation to CD8 T cells

HIV-1 Tat Length: Comparative and Functional Considerations

HDACi mediate UNG2 depletion, dysregulated genomic uracil and altered expression of oncoproteins and tumor suppressors in B- and T-cell lines

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