HIV-1 Infection Downregulates Nuclear Telomerase Activity on Lymphoblastoic Cells Without Affecting the Enzymatic Components at the Transcriptional Level

In recent years, more and more evidence has emerged showing that changes in copy number variations (CNVs) correlated with the transcriptional level can be found during evolution, embryonic development, and oncogenesis. However, the underlying mechanisms remain largely unknown. The success of the induced pluripotent stem cell suggests that genome changes could bring about transformations in protein expression and cell status; conversely, genome alterations generated during embryonic development and senescence might also be the result of genome changes. With rapid developments in science and technology, evidence of changes in the genome affected by transcriptional level has gradually been revealed, and a rational and concrete explanation is needed. Given the preference of the HIV-1 genome to insert into transposons of genes with high transcriptional levels, we propose a mechanism based on retrotransposons facilitated by specific pre-mRNA splicing style and homologous recombination (HR) to explain changes in CNVs in the genome. This mechanism is similar to that of the group II intron that originated much earlier. Under this proposed mechanism, CNVs on genome are dynamically and spontaneously extended in a manner that is positively correlated with transcriptional level or contract as the cell divides during evolution, embryonic development, senescence, and oncogenesis, propelling alterations in them. Besides, this mechanism explains several critical puzzles in these processes. From evidence collected to date, it can be deduced that the message contained in genome is not just three-dimensional but will become four-dimensional, carrying more genetic information.

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Faculty Opinions recommendation of Telomerase activity of HIV-1-specific CD8+ T cells: constitutive up-regulation in controllers and selective increase by blockade of PD ligand 1 in progressors.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1119429.575620 ◽

2008 ◽

Author(s):

Paul Klenerman

Keyword(s):

T Cells ◽

Cd8 T Cells ◽

Telomerase Activity ◽

Selective Increase ◽

Hiv 1

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BCA2/Rabring7 Interferes with HIV-1 Proviral Transcription by Enhancing the SUMOylation of IκBα

Journal of Virology ◽

10.1128/jvi.02098-16 ◽

2017 ◽

Vol 91 (8) ◽

Cited By ~ 9

Author(s):

Marta Colomer-Lluch ◽

Ruth Serra-Moreno

Keyword(s):

New Drugs ◽

Host Cells ◽

Transcriptional Level ◽

Lysosomal Degradation ◽

Virus Propagation ◽

Independent Manner ◽

Virion Assembly ◽

Sumo Ligase ◽

Additional Barrier ◽

Hiv 1

ABSTRACT BCA2/Rabring7 is a BST2 cofactor that promotes the lysosomal degradation of trapped HIV-1 virions but also functions as a BST2-independent anti-HIV factor by targeting Gag for lysosomal degradation. Since many antiviral factors regulate the NF-κB innate signaling pathway, we investigated whether BCA2 is also connected to this proinflammatory cascade. Here, we show for the first time that BCA2 is induced by NF-κB-activating proinflammatory cytokines and that upregulation of BCA2 provides regulatory negative feedback on NF-κB. Specifically, BCA2 serves as an E3 SUMO ligase in the SUMOylation of IκBα, which in turn enhances the sequestration of NF-κB components in the cytoplasm. Since HIV-1 utilizes NF-κB to promote proviral transcription, the BCA2-mediated inhibition of NF-κB significantly decreases the transcriptional activity of HIV-1 (up to 4.4-fold in CD4+ T cells). Therefore, our findings indicate that BCA2 poses an additional barrier to HIV-1 infection: not only does BCA2 prevent assembly and release of nascent virions, it also significantly restricts HIV-1 transcription by inhibiting the NF-κB pathway. IMPORTANCE Understanding the interactions between HIV-1 and its host cells is highly relevant to the design of new drugs aimed at eliminating HIV-1 from infected individuals. We have previously shown that BCA2, a cofactor of BST2 in the restriction of HIV-1, also prevents virion assembly in a BST2-independent manner. In this study, we found that BCA2 negatively regulates the NF-κB pathway—a signaling cascade necessary for HIV-1 replication and infectivity—which in turn detrimentally affects proviral transcription and virus propagation. Thus, our results indicate that, besides its previously described functions as an antiviral factor, BCA2 poses an additional barrier to HIV-1 replication at the transcriptional level.

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TIP110/p110nrb/SART3/p110 regulation of hematopoiesis through CMYC

Blood ◽

10.1182/blood-2010-12-325332 ◽

2011 ◽

Vol 117 (21) ◽

pp. 5643-5651 ◽

Cited By ~ 18

Author(s):

Ying Liu ◽

Khalid Timani ◽

Charlie Mantel ◽

Yan Fan ◽

Giao Hangoc ◽

...

Keyword(s):

Active Drug ◽

Rna Binding ◽

Transcriptional Level ◽

Wild Type ◽

Interacting Protein ◽

Hematopoietic Stem ◽

Human Cd34 ◽

Cd34 Cells ◽

Hiv 1 ◽

Wild Type Control

Abstract Intracellular factors are involved in and essential for hematopoiesis. HIV-1 Tat-interacting protein of 110 kDa (TIP110; p110nrb/SART3/p110) is an RNA-binding nuclear protein implicated in the regulation of HIV-1 gene and host gene transcription, pre-mRNA splicing, and cancer immunology. In the present study, we demonstrate a role for TIP110 in the regulation of hematopoiesis. TIP110 was expressed in human CD34+ cells and decreased with differentiation of CD34+ cells. TIP110 mRNA was also expressed in phenotyped mouse marrow hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs). Using TIP110 transgenic (TIP110TG) and haploinsufficient (TIP110+/−) mice, we found that increased TIP110 expression enhanced HPC numbers, survival, and cell cycling, whereas decreased TIP110 expression had the opposite effects. Moreover, TIP110+/− bone marrow HPCs responded more effectively, and TIP110TG HPCs less effectively, than those of wild-type control mice to recovery from the cell-cycle–active drug 5-fluorouracil (5-FU). Unexplained sex differences were noted in HSC competitive repopulating ability, but not HPC numbers, in TIP110TG mice. Intracellularly, TIP110 regulated CMYC and GATA2 expression at the transcriptional level, and TIP110 and CMYC reciprocally regulated the expression of each other. These results demonstrate a role for TIP110 in the regulation of hematopoiesis, effects that are likely linked to TIP110 regulation of CMYC.

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Systemic HIV-1 Infection Produces a Unique Glial Footprint in Humanized Mouse Brains

10.1101/178285 ◽

2017 ◽

Author(s):

Weizhe Li ◽

Santhi Gorantla ◽

Howard E. Gendelman ◽

Larisa Y. Poluektova

Keyword(s):

Mouse Model ◽

Mouse Brain ◽

Human Leukocyte ◽

Therapeutic Interventions ◽

Intraventricular Injection ◽

Transcriptional Level ◽

Humanized Mouse ◽

Hematopoietic Stem ◽

Hiv 1 ◽

Human Specific

AbstractStudies of innate glial cell responses for progressive human immunodeficiency virus type one (HIV-1) infection are hindered by the availability of relevant small-animal models. To overcome this hindrance, a mouse model reconstituted with humanized brain and immune systems was created. Newborn NOD/SCID/IL2Rγc-/- mice of both sexes were transplanted with human neuroglial progenitors (NPC) and hematopoietic stem cells. Intraventricular injection of NPC yielded an anatomical symmetrical glia (human astrocyte and oligodendrocyte) repopulation of the mouse brain. The human glia were observed in periventricular areas, white matter tracts, the olfactory bulb and brain stem. HIV-1 infection of these dual humanized mice led to meningeal and perivascular human leukocyte infiltration into brain. The species-specific viral-neuroimmune interactions in the infected animals were identified by deep RNA sequencing. In the corpus callosum and hippocampus overlapping human-specific transcriptional alterations were seen for interferon type 1 and 2 signaling pathways (STAT1, 2, IRF9, ISG15, IFI6) and a range of host antiviral responses (MX1, OAS1, RSAD2, BST2, SAMHD1) in infected animals. Glial cytoskeleton reorganization, oligodendrocyte differentiation and myelin ensheathment (MBP, MOBP, PLP1, MAG and ZNF488) were downregulated. The data sets were confirmed by real-time PCR. The viral defense signaling patterns observed in these mice parallels the neuroimmune communication networks present in the HIV-1 infected human brain. In this manner, the new mouse model can facilitate discovery of therapeutics, viral eradication targets for virus induced nervous system diseases, and simplify HIVCure research approaches.Summary StatementWe created mice with both a humanized brain and an immune system. The animals were used to investigate glial responses to HIV-1 infection. At a transcriptional level we defined the interactions between human glia and immune cells in the presence of the systemic HIV-1 infection. Noticeably, altered transcriptional changes were human specific. At five weeks after viral infection humanized mouse brain displayed potent interferon-mediated antiviral innate immune responses and alteration of neuronal progenitors differentiation and myelination. This model can be used to tests both diagnostic and therapeutic interventions for cure HIV-associated brain impairment.

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Human Immunodeficiency Virus Induces a Dual Regulation of Bcl-2, Resulting in Persistent Infection of CD4+ T- or Monocytic Cell Lines

Journal of Virology ◽

10.1128/jvi.72.12.9698-9705.1998 ◽

1998 ◽

Vol 72 (12) ◽

pp. 9698-9705 ◽

Cited By ~ 61

Author(s):

Fabienne Aillet ◽

Hiroshi Masutani ◽

Carole Elbim ◽

Hervé Raoul ◽

Laurent Chêne ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Persistent Infection ◽

Protein Level ◽

Cellular Protein ◽

Transcriptional Level ◽

Monocytic Cell ◽

Transient Decrease ◽

Immunodeficiency Virus ◽

Kinetics Of ◽

Hiv 1

ABSTRACT This work aims at characterizing the interplay between human immunodeficiency virus type 1 (HIV-1) and the antiapoptotic cellular protein Bcl-2 responsible for a persistent infection in lymphoblastoid T (J.Jhan) or monocytic (U937) cells. We report that the kinetics of Bcl-2 protein level during the establishment of a chronic infection is biphasic, characterized by a transient decrease followed by restoration to the initial level. The extent and duration of this transient decrease were inversely correlated with the basal level of Bcl-2 as shown by kinetics of Bcl-2 levels in J.Jhan or U937 clones exhibiting different levels of Bcl-2. Using these clones, we also showed that Bcl-2 downregulates HIV-1 replication. Therefore, the cells overexpressing Bcl-2 are characterized by a low viral burden which, in turn, has little effect on the level of this protein. The observed bipasic kinetics is the result of a dual regulation of Bcl-2 induced by HIV-1 infection itself: an upregulation at the transcriptional level of the bcl-2 gene concomitant with a downregulation at the protein level. Convergent data suggest that this downregulation is caused by the oxidative stress induced by the infection itself as shown by the associated modulations of glutathione and thioredoxin levels and by the prevention of these dysregulations byN-acetylcysteine. Altogether, these data indicate that infection first results in a decrease of Bcl-2, permitting an initial boost of replication. Then, as the synthesis at the transcriptional level proceeds, the replication is negatively controlled by Bcl-2 to reach a balance characterized by low virus production and a level of Bcl-2 compatible with cell survival. We suggest that the basal level of Bcl-2, together with infection-inducible transcription factors able to activate bcl-2 gene transcription, is a critical cellular determinant in the tendency toward an acute or a persistent infection.

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Molecular mechanisms involved in HIV-1-Tat mediated inhibition of telomerase activity in human CD4+ T lymphocytes

Molecular Immunology ◽

10.1016/j.molimm.2012.12.003 ◽

2013 ◽

Vol 54 (2) ◽

pp. 181-192 ◽

Cited By ~ 16

Author(s):

Alessandro Comandini ◽

Chiara Naro ◽

Riccardo Adamo ◽

Arne N. Akbar ◽

Alessio Lanna ◽

...

Keyword(s):

T Lymphocytes ◽

Molecular Mechanisms ◽

Telomerase Activity ◽

Hiv 1

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Telomere Length Shortening in Microglia: Implication for Accelerated Senescence and Neurocognitive Deficits in HIV

Vaccines ◽

10.3390/vaccines9070721 ◽

2021 ◽

Vol 9 (7) ◽

pp. 721

Author(s):

Chiu-Bin Hsiao ◽

Harneet Bedi ◽

Raquel Gomez ◽

Ayesha Khan ◽

Taylor Meciszewski ◽

...

Keyword(s):

Oxidative Stress ◽

Telomere Length ◽

Mitochondrial Function ◽

Immune Cells ◽

Telomerase Activity ◽

Microglial Cells ◽

Neurocognitive Deficits ◽

Telomere Shortening ◽

Hiv Tat ◽

Hiv 1

The widespread use of combination antiretroviral therapy (cART) has led to the accelerated aging of the HIV-infected population, and these patients continue to have a range of mild to moderate HIV-associated neurocognitive disorders (HAND). Infection results in altered mitochondrial function. The HIV-1 viral protein Tat significantly alters mtDNA content and enhances oxidative stress in immune cells. Microglia are the immune cells of the central nervous system (CNS) that exhibit a significant mitotic potential and are thus susceptible to telomere shortening. HIV disrupts the normal interplay between microglia and neurons, thereby inducing neurodegeneration. HIV cART contributes to the inhibition of telomerase activity and premature telomere shortening in activated peripheral blood mononuclear cells (PBMC). However, limited information is available on the effect of cART on telomere length (TL) in microglia. Although it is well established that telomere shortening induces cell senescence and contributes to the development of age-related neuro-pathologies, the effect of HIV-Tat on telomere length in human microglial cells and its potential contribution to HAND are not well understood. It is speculated that in HAND intrinsic molecular mechanisms that control energy production underlie microglia-mediated neuronal injury. TL, telomerase and mtDNA expression were quantified in microglial cells using real time PCR. Cellular energetics were measured using the Seahorse assay. The changes in mitochondrial function were examined by Raman Spectroscopy. We have also examined TL in the PBMC obtained from HIV-1 infected rapid progressors (RP) on cART and those who were cART naïve, and observed a significant decrease in telomere length in RP on cART as compared to RP’s who were cART naïve. We observed a significant decrease in telomerase activity, telomere length and mitochondrial function, and an increase in oxidative stress in human microglial cells treated with HIV Tat. Neurocognitive impairment in HIV disease may in part be due to accelerated neuro-pathogenesis in microglial cells, which is attributable to increased oxidative stress and mitochondrial dysfunction.

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