Both Human immunodeficiency virus (HIV) and Epstein-Barr Virus (EBV) are associated with an increased risk of malignancies. HIV infection is associated with EBV reactivation and an increase in EBV viral loads in saliva and blood, and people living with HIV frequently develop EBV-associated B-cell malignancies. In this study, we aimed to investigate the involvement of HIV-1 and EBV co-existence in the development of B-cell malignancies. To do so, we focused our attention on the two viral transcriptional activators (HIV-1 Tat and EBV Zta) and analyzed their possible interaction since they both have cell-penetration domains and can be found simultaneously in the blood or cells of people living with HIV. We investigated the interaction of Tat and Zta using co-immunoprecipitation, in vitro binding, YFP reconstitution assay and FRET. We found that they bind each other in human B cells and blood serum. Tat and Zta interaction was also observed in a serum sample from one HIV-positive individual. YFP reconstitution demonstrated that this interaction occurred predominantly in the nucleus, indicating that it might affect the host genome. We further analyzed the effects of Tat and Zta on primary and EBV-transformed human B cells by RNA-sequencing and found that the combined Tat and Zta action in B cells differed from a single action of the two proteins. A subset of genes, activated by Tat or Zta alone, that trigger an immune response and antigen presentation in B cells, remained unchanged when the two proteins were combined. B cells, treated or transfected with Tat and Zta, exhibited a substantial decrease in HLA-ABC (MHC class I) expression, a critical component of the antigen processing and presentation pathway. Our findings suggest that the reduction of total HLA-ABC levels in B cells upon Tat and Zta interaction might be linked to HLA-ABC proteasomal degradation. Furthermore, HLA-ABC downregulation induced by Tat and Zta interaction conferred protection against cytotoxic T cell recognition of EBV-infected B cells. To conclude, we demonstrated for the first time that HIV-1 Tat and EBV Zta interacted directly in B cells and blood serum; this interaction can be found in people with HIV. This interaction brings about immune evasion of EBV-infected or transformed B cells.

ABSTRACT Mantle cell lymphoma (MCL) is defined by the t(11;14)(q13;q32) translocation, which drives constitutive CCND1 expression, yet the broader regulatory consequences of this rearrangement remain incompletely understood. Here, we combined transcriptomic, epigenomic, Hi-C, and 3D-FISH analyses in primary MCL samples and cell lines to investigate the genome-wide impact of t(11;14) on chromatin organization and gene regulation beyond the rearranged chromosomes. We show that MCL cells exhibit widespread enhancer activation, accompanied by expansion of super-enhancer regions. The translocated CCND1 locus repositions toward the nuclear interior and acquires enhancer-like features. Genome-wide analysis highlighted chromosome 19 as a hotspot of transcriptional upregulation. Notably, Hi-C and 3D-FISH revealed recurrent interchromosomal contacts between chromosome 19 and the CCND1 locus, preferentially involving the derivative chromosome. These contacts colocalize with active RNA polymerase II and are associated with increased expression of nearby chr19 genes, suggesting an association between spatial proximity and transcriptional activation in trans. Minnelide treatment reduced chromatin accessibility at the CCND1 locus, decreased the frequency of chr19-der14 interactions, and partially reversed the MCL transcriptional program, while exerting strong anti-tumor effects in vitro and in vivo . Together, these findings identify a recurrent interchromosomal interaction associated with coordinated gene activation in MCL and suggest that spatial genome reorganization contributes to disease-specific transcriptional programs.

PEP-010 is a pro-apoptotic peptide based on a proprietary cell-penetrating and interfering peptide technology for the treatment of advanced solid tumors. PEP-010 acts by disrupting the interaction between caspase-9 and PP2A, two key proteins involved in apoptosis, a physiological process frequently altered in cancers. PEP-010 efficiently induces apoptosis in cancer cells. PEP-010 demonstrates antitumor activity by inhibiting the growth of breast cancer patient-derived xenografts (PDX). This study establishes cleaved caspase-3 and Ki67 protein expression as two candidate pharmacodynamic (PD) biomarkers for monitoring PEP-010-induced apoptosis in vitro and in vivo.

OBJECTIVES:Despite successful human immunodeficiency virus (HIV) control with combination antiretroviral therapy (cART), individuals with HIV still face health risks, including cancers, cardiovascular and neurocognitive diseases. An HIV protein, Tat, is potentially involved in these HIV-related diseases. Previous studies demonstrated circulating Tat in the blood of untreated people with HIV. Here, we measured Tat levels in the serum of cART-treated people with HIV to examine the effect of cART on Tat production.METHODS:Serum samples from 63 HIV-positive and 20 HIV-seronegative individuals were analyzed using an ELISA assay that detected Tat concentrations above 2.5 ng/mL.RESULTS:Among HIV-positive individuals, the Tat level ranged from 0 to 14 ng/mL. 25.4% (16 out of 63) exceeded the 2.5 ng/mL cut-off, with a median HIV Tat level of 4.518 [3.329-8.120] ng/mL. No correlation was revealed between Tat levels and CD4+ T cell counts, serum HIV RNA, p24 antigen, or anti-Tat levels.CONCLUSIONS:Despite cART, circulating HIV Tat persists and may contribute to HIV-related diseases. This emphasizes the need for further research on the mechanisms of Tat action in non-infected cells where it can penetrate upon circulation in the blood.

Ovarian adenocarcinoma is the gynecological malignancy with the worst prognosis and the highest mortality rate. In the first stages of treatment, chemotherapy results effective, but its prolonged use and high doses lead to the appearance of resistance to treatments and relapse in most patients, representing a major challenge for clinicians. We developed PEP-010, a cell penetrating proapoptotic peptide disrupting the protein-protein interaction between caspase-9 and protein phosphatase 2A, thereby leading to the recovery of their activity in the apoptotic pathway. MTT assay or Annexin-V/Propidium Iodide staining and flow cytometry analysis were used to assess sensitivity to chemotherapies and apoptosis after treatment with PEP-010 in monotherapy or in combination with paclitaxel in ovarian carcinoma cell lines. DNA damage was assessed by immunofluorescence using γH2AX marker. We show here that PEP-010 effectively induces cell death in monotherapy on in up to 55% of cells from ovarian adenocarcinoma cell models resistant to different chemotherapies. Moreover, when used in combination with paclitaxel, one of the therapeutic options for recurrent ovarian carcinoma, PEP-010 showed a beneficial effect leading to the reduction of the IC50 of paclitaxel of 2.2 times and to apoptosis in 87% of cells. The described results suggest the potential therapeutic interest for PEP-010 and lead to the choice of ovarian adenocarcinoma as one of the major indications of the ongoing clinical trial.

Despite the success of combination antiretroviral therapy, people living with human immunodeficiency virus (HIV) still have an increased risk of Epstein-Barr virus (EBV)-associated B cell malignancies. In the HIV setting, B cell physiology is altered by coexistence with HIV-infected cells and the chronic action of secreted viral proteins, for example, HIV-1 Tat that, once released, efficiently penetrates noninfected cells. We modeled the chronic action of HIV-1 Tat on B cells by ectopically expressing Tat or TatC22G mutant in two lymphoblastoid B cell lines. The RNA-sequencing analysis revealed that Tat deregulated the expression of hundreds of genes in B cells, including the downregulation of a subset of major histocompatibility complex (MHC) class II-related genes. Tat-induced downregulation of HLA-DRB1 and HLA-DRB5 genes led to a decrease in HLA-DR surface expression; this effect was reproduced by coculturing B cells with Tat-expressing T cells. Chronic Tat presence decreased the NF-kappa B pathway activity in B cells; this downregulated NF-kappa B-dependent transcriptional targets, including MHC class II genes. Notably, HLA-DRB1 and surface HLA-DR expression was also decreased in B cells from people with HIV. Tat-induced HLA-DR downregulation in B cells impaired EBV-specific CD4+ T cell response, which contributed to the escape from immune surveillance and could eventually promote B cell lymphomagenesis in people with HIV.

In cancer cells, the proapoptotic proteins caspase-9 and PP2A interaction prevents them to play their role in apoptosis. PEP-010, a drug candidate developed by PEP-Therapy, a French Biotech company, is a proapoptotic peptide targeting and disrupting this interaction leading to restoration of the apoptotic cascade. PEP-010 is an innovative bifunctional peptide. It penetrates into cells thanks to its cell penetrating part and specifically disrupts the caspase-9/PP2A interaction thanks to its interfering part. PEP-010 is currently in Phase I a/b multicenter clinical trial for the treatment of advanced solid tumors.To the aim of screening different potential therapeutic targets, to investigate the molecular mechanism-of-action of PEP-010 and to identify potential pharmacodynamic biomarkers, we have tested PEP-010 efficacy on several cell models of different tumor origins. By the Annexin V/Propidium Iodide staining and flow cytometry analysis, we found that PEP-010 induces apoptosis in most of the tested models. One possible mechanism-of-action is an involvement of the PP2A which, once released by PEP-010, could regulate expression and/or activity of different intracellular factors leading to caspases activation and cell death.The identification of the major molecular features involved in PEP-010 mechanism-of-action, were instrumental to identify different pharmacodynamic biomarker candidates (e.g. active caspase-3). Hence, such biomarkers could be useful in clinical practice to monitor the effect of PEP-010 at molecular level. We have compared specific features related to the mechanism-of-action of PEP-010 in sensitive (MDA-MB-231, IGROV1) and not sensitive cell models of different tumor origins and in tissue sections derived from Patient-Derived Xenografts models of breast cancer treated or not with PEP-010. Widely used techniques as immunofluorescent staining and immunohistochemistry were employed, making these results easily transferable in clinical routine.Taken together, our pre-clinical data showed the potential of PEP-010 as an anti-cancer peptide on a wide variety of malignancies and enabled the identification of pharmacodynamic biomarker candidates, important to ease the clinical development. Citation Format: Rayan Farhat, Laura Dadon, F Nemati, A Rebollo, D Decaudin, Joelle Wiels, Catherine Brenner, Diego Germini. The proapoptotic peptide PEP-010 is efficient on several models of different tumor origins and it can be monitored by pharmacodynamic biomarker candidates in clinical practice. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6129.

Abstract In cancer cells, the proapoptotic proteins caspase-9 and PP2A interaction prevents them to play their role in apoptosis. PEP-010, a drug candidate developed by PEP-Therapy, a French Biotech company, is a proapoptotic peptide targeting and disrupting this interaction leading to restoration of the apoptotic cascade. PEP-010 is an innovative bifunctional peptide. It penetrates into cells thanks to its cell penetrating part and specifically disrupts the caspase-9/PP2A interaction thanks to its interfering part. PEP-010 is currently in Phase I a/b multicenter clinical trial for the treatment of advanced solid tumors.To the aim of screening different potential therapeutic targets, to investigate the molecular mechanism-of-action of PEP-010 and to identify potential pharmacodynamic biomarkers, we have tested PEP-010 efficacy on several cell models of different tumor origins. By the Annexin V/Propidium Iodide staining and flow cytometry analysis, we found that PEP-010 induces apoptosis in most of the tested models. One possible mechanism-of-action is an involvement of the PP2A which, once released by PEP-010, could regulate expression and/or activity of different intracellular factors leading to caspases activation and cell death.The identification of the major molecular features involved in PEP-010 mechanism-of-action, were instrumental to identify different pharmacodynamic biomarker candidates (e.g. active caspase-3). Hence, such biomarkers could be useful in clinical practice to monitor the effect of PEP-010 at molecular level. We have compared specific features related to the mechanism-of-action of PEP-010 in sensitive (MDA-MB-231, IGROV1) and not sensitive cell models of different tumor origins and in tissue sections derived from Patient-Derived Xenografts models of breast cancer treated or not with PEP-010. Widely used techniques as immunofluorescent staining and immunohistochemistry were employed, making these results easily transferable in clinical routine.Taken together, our pre-clinical data showed the potential of PEP-010 as an anti-cancer peptide on a wide variety of malignancies and enabled the identification of pharmacodynamic biomarker candidates, important to ease the clinical development. Citation Format: Rayan Farhat, Laura Dadon, F Nemati, A Rebollo, D Decaudin, Joelle Wiels, Catherine Brenner, Diego Germini. The proapoptotic peptide PEP-010 is efficient on several models of different tumor origins and it can be monitored by pharmacodynamic biomarker candidates in clinical practice. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6129.

Abstract Most cancer-related chromosomal translocations appear to be cell type specific. It is currently unknown why different chromosomal translocations occur in different cells. This can be due to either the occurrence of particular translocations in specific cell types or adaptive survival advantage conferred by translocations only in specific cells. We experimentally addressed this question by double-strand break (DSB) induction at MYC, IGH, AML and ETO loci in the same cell to generate chromosomal translocations in different cell lineages. Our results show that any translocation can potentially arise in any cell type. We have analyzed different factors that could affect the frequency of the translocations, and only the spatial proximity between gene loci after the DSB induction correlated with the resulting translocation frequency, supporting the ‘breakage-first’ model. Furthermore, upon long-term culture of cells with the generated chromosomal translocations, only oncogenic MYC–IGH and AML–ETO translocations persisted over a 60-day period. Overall, the results suggest that chromosomal translocation can be generated after DSB induction in any type of cell, but whether the cell with the translocation would persist in a cell population depends on the cell type-specific selective survival advantage that the chromosomal translocation confers to the cell.

Burkitt lymphoma (BL) is a B cell malignancy associated with the Epstein-Barr virus (EBV). Most BL cases are characterized by a t(8;14) chromosomal translocation involving the MYC oncogene and the immunoglobulin heavy chain gene (IGH). The role of EBV in promoting this translocation remains largely unknown. Here we provide the experimental evidence that EBV reactivation from latency leads to an increase in the proximity between the MYC and IGH loci, otherwise located far away in the nuclear space both in B-lymphoblastoid cell lines and in patients' B-cells. Specific DNA damage within the MYC locus, followed by the MRE11-dependent DNA repair plays a role in this process. Using a CRISPR/Cas9-based B cell model to induce specific DNA double strand breaks in MYC and IGH loci, we have shown that the MYC-IGH proximity induced by EBV reactivation leads to an increased t(8;14) translocation frequency.

An increased frequency of B-cell lymphomas is observed in human immunodeficiency virus-1 (HIV-1)-infected patients, although HIV-1 does not infect B cells. Development of B-cell lymphomas may be potentially due to the action of the HIV-1 Tat protein, which is actively released from HIV-1-infected cells, on uninfected B cells. The exact mechanism of Tat-induced B-cell lymphomagenesis has not yet been precisely identified. Here, we ectopically expressed either Tat or its TatC22G mutant devoid of transactivation activity in the RPMI 8866 lymphoblastoid B cell line and performed a genome-wide analysis of host gene expression. Stable expression of both Tat and TatC22G led to substantial modifications of the host transcriptome, including pronounced changes in antiviral response and cell cycle pathways. We did not find any strong action of Tat on cell proliferation, but during prolonged culturing, Tat-expressing cells were displaced by non-expressing cells, indicating that Tat expression slightly inhibited cell growth. We also found an increased frequency of chromosome aberrations in cells expressing Tat. Thus, Tat can modify gene expression in cultured B cells, leading to subtle modifications in cellular growth and chromosome instability, which could promote lymphomagenesis over time.

Chromosomal translocations are products of the illegitimate repair of DNA double-strand breaks (DSBs). Their formation can bring about significant structural and molecular changes in the cell that can be physiologically and pathologically relevant. The induced changes may lead to serious and life-threatening diseases such as cancer. As a growing body of evidence suggests, the formation of chromosomal translocation is not only affected by the mere close spatial proximity of gene loci as potential translocation partners. Several factors may affect formation of chromosomal translocations, including chromatin motion to the potential sources of DSBs in the cell. While these can be apparently random events, certain chromosomal translocations appear to be cell-type-specific. In this review, we discuss how chromosomal translocations are formed and explore how different cellular factors contribute to their formation.

Dear Editor, Chromosomal translocations result from the interchange of genetic material between non-homologous chromosomes. Chromosomal translocations are formed by erroneous repair of double-stranded breaks (DSBs) via non-homologous end joining (NHEJ) [1]. Some genotoxic drugs produce DSBs and thus present a major risk factor for the development of oncogenic chromosomal translocations. The risk factors that interfere with translocation-prone DSB repair, once DSBs are already formed, are obscure, and potential effects of drugs on translocation formation during this step have never been explored. The study of chromosomal translocations is complicated since naturally occurring translocations are rare, and the localization of breakpoints varies from kilobases to hundreds of kilobases, which complicates their detection. In contrast, when DSBs are generated at precise loci, the translocation can be easily detected by PCR. In the present work, we developed two experimental human B cell-based models to study lymphomagenic t(8;14) MYC-IGH and leukemogenic t(8;21) AML1-ETO translocations, characteristic for Burkitt's lymphoma (BL) [2] and acute myeloid leukemia (AML), respectively [3]. We used these systems to study pathways and drugs that affect the probability of oncogenic translocations. BL often arises in people living with human immunodeficiency virus (HIV, PLWH) who are treated with combination antiretroviral therapy regimen [4], while chemotherapy is a risk factor for secondary AML [3]; therefore, we tested common antiretroviral and chemotherapeutic drugs for their ability to influence the rate of translocation formation in our systems. Two experimental systems for the targeted generation of DSBs in either the AML1 and ETO (iAML1-ETO cell line) or MYC and IGH loci (iMYC-IGH cell line) were created. The models were derived from the RPMI8866 lymphoblastoid cell line with the stable integration of the Cas9 gene, expressed under the control of a doxycycline (Dox)-inducible promoter and two guide RNA genes (targeting either AML1-ETO or MYC-IGH loci) (Figure 1A, Supplementary Figure S1). The DSB loci in the AML1-ETO model were similar to breakpoints in patients with therapy-related AML and cells treated with etoposide; the DSB loci in the MYC-IGH model were similar to breakpoints in patients with sporadic and HIV-induced BL (see Supplementary Methods for further information). The addition of Dox activated Cas9 expression after 4 hours (Figure 1B, Supplementary Figure S2) and stimulated the formation of DSBs in the selected loci (data not shown). The generated t(8;14) or t(8;21) translocations were detectable by qPCR using the primers that surrounded the translocation breakpoint (Figure 1C-D, Supplementary Figure S3). Translocations peaked after 48 hours for iMYC-IGH and 96 hours for iAML1-ETO (data not shown), and these timepoints were selected for further experiments. Without Dox treatment, chromosomal translocations were undetectable. To get insight into the mechanisms of the translocation generation in our system, we used several inhibitors of DSB repair pathways. iMYC-IGH cells were simultaneously treated with Dox and either Mirin (an MRE11 inhibitor), KU-55933 [(an ataxia telangiectasia mutated (ATM) inhibitor)], 17-N-allylamino-17-demethoxygeldanamycin [17-AAG, an Hsp90 inhibitor that inhibits homologous recombination (HR) repair by destabilizing Rad51], NU7026 [a DNA-dependent protein kinase (DNA-PK) inhibitor, classical NHEJ, (c-NHEJ)], or L67 [an inhibitor of DNA ligase I and III, alternative NHEJ (a-NHEJ)]. Treatment with Mirin, KU-55933 or L67 significantly decreased, whereas treatment with NU7026 significantly increased the MYC-IGH translocation rate (Figure 1E). Presumably, the inhibition of MRE11 and ATM, involved in the early steps of DNA damage detection and response, resulted in DSB repair defects [5] and ultimately cell cycle arrest or death, which decreased the overall translocation rates. ATM also promotes the clustering of DSBs into large repair foci [5], which might contribute to DSB proximity and translocations. The inhibition of c-NHEJ increased the translocation rate, while the inhibition of the a-NHEJ pathway decreased the translocation rate, which were in agreement with a previous studies [1]. The increase in the translocation rate when c-NHEJ is abrogated is due to the slow kinetics of DNA repair via a-NHEJ, which permits the free movement of unrepaired DNA ends and increases the chance of meeting their translocation partner in the nuclear space [1]. We next tested whether some chemotherapeutic drugs could influence the translocation formation and thus contribute to the formation of secondary neoplasms, e.g., therapy-related AML. We used drugs of different classes: platinum-based antineoplastics (carboplatin, cisplatin, oxaliplatin), topoisomerase inhibitors (doxorubicin, etoposide, irinotecan, mitoxantrone), antimetabolites (cytarabine, fluorouracil, methotrexate), poly(ADP-ribose) polymerase (PARP) inhibitor (olaparib), an alkylating agent (ifosfamide), and cytoskeletal drugs (docetaxel, paclitaxel). To exclude the effects related to cytotoxicity and cell death, we chose the non-lethal 10% inhibitory concentration (IC10) of the above drugs (Supplementary Table S3, Supplementary Figure S4). iAML1-ETO cells were simultaneously treated with Dox and chemotherapeutic drugs, and the level of t(8;21) translocations was measured and compared to those in Dox-treated cells. We found that the addition of methotrexate increased more than two-fold the rate of AML1-ETO translocations (Figure 1F). No significant differences were found for other drugs, which was further confirmed in iMYC-IGH cells with five other chemotherapeutic drugs used at IC10. No significant differences were found between the translocation rate in Dox-treated and Dox+drug-treated iMYC-IGH cells (Figure 1G). These results indicated that in the iMYC-IGH model, chemotherapeutic drugs did not interfere with the DSB repair once DSBs were formed. Thus, methotrexate use can increase the risk of secondary therapy-related AML, and patients treated with methotrexate should be monitored for the development of AML. Noteworthy, the development of therapy-related myelodysplastic syndrome/AML with t(8;21) and t(3;21) translocations was described in patients following low-dose treatment with methotrexate for rheumatoid arthritis [6]. We next tested whether antiretroviral drugs could influence the level of MYC-IGH translocations since BL is a common neoplasm in PLWH. We used drugs from different classes, such as nucleoside reverse transcriptase inhibitors (NRTIs) [abacavir (ABC), azidothymidine (AZT), emtricitabine (FTC), lamivudine (3TC)], non-NRTIs (nevirapine, rilpivirine), protease inhibitors (amprenavir, atazanavir, indinavir, saquinavir), and C-C motif chemokine receptor 5 (CCR5) antagonist (TAK779). The drugs were added simultaneously with Dox to the iMYC-IGH cell medium at the reported IC50 for virus inhibition. The chosen concentrations were not toxic for the cells (Supplementary Figure S4C). We found that two NRTIs, ABC and FTC, and CCR5 antagonist TAK779 significantly increased the rate of MYC-IGH translocations (Figure 1H). NTRIs are known to be incorporated into nuclear DNA by certain DNA polymerases during DNA repair, and they can act as chain terminators and directly inhibit cellular DNA polymerases by binding to their catalytic site [7]. Compromised DNA damage response may delay the classical repair machinery and engage translocation-prone a-NHEJ. Furthermore, mitochondrial toxicity of NRTIs could affect nuclear DNA integrity through reactive oxygen species production and imbalanced deoxynucleoside triphosphate pools [8]. CCR5 governs DNA damage repair (HR and single-strand annealing); consequently, CCR5 inhibitors were shown to sensitize cells to DNA-damaging agents [9]. Defects in HR and c-NHEJ repair mechanisms can result in chromosomal translocations [1]. A phase II clinical study of vicriviroc, a CCR5 antagonist, showed that vicriviroc treatment was associated with an increased risk of developing lymphomas [10]. Vicriviroc was not approved for HIV treatment. To conclude, we developed CRISPR/Cas9-based cell models with inducible AML1-ETO and MYC-IGH translocations to evaluate the potential of drugs to favor secondary translocations. In our screen, we identified four drugs, methotrexate, ABC, FTC and TAK779, that increased the rate of chromosomal translocations. A.S. and N.L. performed the following experiments: cell line creation and characterization, experimental setup, translocation rate analysis, survival analysis, RT-qPCR, western blotting, analyzed data and wrote the paper; D.S. and V.P. performed the following experiments: translocation rate and survival analysis and contributed new reagents; V.V., T.T., D.G. and Y.K. performed the following experiments: translocation rate analysis, RT-qPCR, western blotting; M.S. and M.R. analyzed data; Y.V. designed research, analyzed data and wrote the paper. This study was supported by Cancéropole IdF, the Koltzov Institute of Developmental Biology, Russian Academy of Sciences Government basic research programs (0088-2021-0007) and the Ministry of Science and Higher Education grants (075-15-2021-1075 to YV and 075-15-2021-1062 and 075-15-2021-1060 to MR); Russian Foundation for Basic Research (19-54-16002) and by the Interdisciplinary Scientific and Educational School of Moscow University «Molecular Technologies of the Living Systems and Synthetic Biology» to MR. AS was supported by the Travel Grant from Boehringer Ingelheim Fonds in 2018. The authors declare that they have no competing interests Methods and materials are available in the supplementary file. All data generated or analyzed during this study are included in this published article and its supplementary information files. 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HIV-1 infects T cells, but the most frequent AIDS-related lymphomas are of B-cell origin. Molecular mechanisms of HIV-1-induced oncogenic transformation of B cells remain largely unknown. HIV-1 Tat protein may participate in this process by penetrating and regulating gene expression in B cells. Both immune and cancer cells can reprogram communications between extracellular signals and intracellular signaling pathways via the Akt/mTORC1 pathway, which plays a key role in the cellular response to various stimuli including viral infection. Here, we investigated the role of HIV-1 Tat on the modulation of the Akt/mTORC1 pathway in B cells. We found that HIV-1 Tat activated the Akt/mTORC1 signaling pathway; this leads to aberrant activation of activation-induced cytidine deaminase (AICDA) due to inhibition of the AICDA transcriptional repressors c-Myb and E2F8. These perturbations may ultimately lead to an increased genomic instability and proliferation that might cause B cell malignancies.

Mammalian and Drosophila genomes are partitioned into topologically associating domains (TADs). Although this partitioning has been reported to be functionally relevant, it is unclear whether TADs represent true physical units located at the same genomic positions in each cell nucleus or emerge as an average of numerous alternative chromatin folding patterns in a cell population. Here, we use a single-nucleus Hi-C technique to construct high-resolution Hi-C maps in individual Drosophila genomes. These maps demonstrate chromatin compartmentalization at the megabase scale and partitioning of the genome into non-hierarchical TADs at the scale of 100 kb, which closely resembles the TAD profile in the bulk in situ Hi-C data. Over 40% of TAD boundaries are conserved between individual nuclei and possess a high level of active epigenetic marks. Polymer simulations demonstrate that chromatin folding is best described by the random walk model within TADs and is most suitably approximated by a crumpled globule build of Gaussian blobs at longer distances. We observe prominent cell-to-cell variability in the long-range contacts between either active genome loci or between Polycomb-bound regions, suggesting an important contribution of stochastic processes to the formation of the Drosophila 3D genome.

HIV infected people are at higher risk of developing cancer, although it is globally diminished in the era of highly active antiretroviral treatment (HAART). Recently, antioncogenic properties of some HAART drugs were discovered. We discuss the role of HAART in the prevention and improvement of treatment outcomes of cancers in HIV‐infected people. We describe different trends in HAART–cancer relationships: cancer‐predisposing as well as cancer‐preventing. We cover the roles of particular drug regimens in cancer prevention. We also describe the causes of cancer treatment with HAART drugs in HIV‐negative people, including ongoing clinical studies that may directly point to a possible independent anti‐oncogenic activity of HAART drugs. We conclude that despite potent antioncogenic activities of every class of HAART drugs reported in preclinical models, the evidence to date indicates that their independent clinical impact in HIV‐infected people is limited. Improved cancer prevention strategies besides HAART are needed to reduce HIV‐cancer‐related mortality.

Epstein Barr Virus (EBV) is one of the most common human herpesviruses. After primary infection, it can persist in the host throughout their lifetime in a latent form, from which it can reactivate following specific stimuli. EBV reactivation is triggered by transcriptional transactivator proteins ZEBRA (also known as Z, EB-1, Zta or BZLF1) and RTA (also known as BRLF1). Here we discuss the structural and functional features of ZEBRA, its role in oncogenesis and its possible implication as a prognostic or diagnostic marker. Modulation of host gene expression by ZEBRA can deregulate the immune surveillance, allow the immune escape, and favor tumor progression. It also interacts with host proteins, thereby modifying their functions. ZEBRA is released into the bloodstream by infected cells and can potentially penetrate any cell through its cell-penetrating domain; therefore, it can also change the fate of non-infected cells. The features of ZEBRA described in this review outline its importance in EBV-related malignancies.