17 results on '"Dash, Chandravanu"'
Search Results
2. The Complex Interaction Between Methamphetamine Abuse and HIV-1 Pathogenesis
- Author
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Passaro, Ryan Colby, Pandhare, Jui, Qian, Han-Zhu, and Dash, Chandravanu
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- 2015
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3. Are microRNAs Important Players in HIV-1 Infection? An Update.
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Balasubramaniam, Muthukumar, Pandhare, Jui, and Dash, Chandravanu
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HIV-positive persons ,ANTIRETROVIRAL agents ,DRUG resistance ,PROTEIN synthesis ,GENE silencing - Abstract
HIV-1 has already claimed over 35 million human lives globally. No curative treatments are currently available, and the only treatment option for over 36 million people currently living with HIV/AIDS are antiretroviral drugs that disrupt the function of virus-encoded proteins. However, such virus-targeted therapeutic strategies are constrained by the ability of the virus to develop drug-resistance. Despite major advances in HIV/AIDS research over the years, substantial knowledge gaps exist in many aspects of HIV-1 replication, especially its interaction with the host. Hence, understanding the mechanistic details of virus-host interactions may lead to novel therapeutic strategies for the prevention and/or management of HIV/AIDS. Notably, unprecedented progress in deciphering host gene silencing processes mediated by several classes of cellular small non-coding RNAs (sncRNA) presents a promising and timely opportunity for developing non-traditional antiviral therapeutic strategies. Cellular microRNAs (miRNA) belong to one such important class of sncRNAs that regulate protein synthesis. Evidence is mounting that cellular miRNAs play important roles in viral replication, either usurped by the virus to promote its replication or employed by the host to control viral infection by directly targeting the viral genome or by targeting cellular proteins required for productive virus replication. In this review, we summarize the findings to date on the role of miRNAs in HIV-1 biology. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
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4. Cocaine Enhances HIV-1 Transcription in Macrophages by Inducing p38 MAPK Phosphorylation.
- Author
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Swepson, Chelsie, Ranjan, Alok, Balasubramaniam, Muthukumar, Pandhare, Jui, Dash, Chandravanu, Khoshbouei, Habibeh, and Kumar, Santosh
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COCAINE ,PHOSPHORYLATION ,MACROPHAGES ,PHYSIOLOGY - Abstract
Cocaine is a commonly used illicit drug among HIV-1 infected individuals and is known to increase HIV-1 replication in permissive cells including PBMCs, CD4C T cells, and macrophages. Cocaine's potentiating effects on HIV-1 replication in macrophagesthe primary targets of the virus in the central nervous system, has been suggested to play an important role in HIV-1 neuro-pathogenesis. However, the mechanism by which cocaine enhances HIV-1 replication in macrophages remain poorly understood. Here, we report the identification of cocaine-induced signaling events that lead to enhanced HIV-1 transcription in macrophages. Treatment of physiologically relevant concentrations of cocaine enhanced HIV-1 transcription in a dose-dependent manner in infected THP-1 monocyte-derived macrophages (THP-1macs) and primary monocytederived macrophages (MDMs). Toward decoding the underlying mechanism, results presented in this report demonstrate that cocaine induces the phosphorylation of p38 mitogen activated protein kinase (p38 MAPK), a known activator of HIV-1 transcription. We also present data suggesting that the p38 MAPK-driven HIV-1 transcription is dependent on the induction of mitogen- and stress-activated protein kinase 1 (MSK1). Consequently, MSK1 mediates the phosphorylation of serine 10 residue of histone 3 (H3 Ser10), which is known to activate transcription of genes including that of HIV- 1 in macrophages. Importantly, our results show that inhibition of p38 MAPK/MSK1 signaling by specific pharmacological inhibitors abrogated the positive effect of cocaine on HIV-1 transcription. These results validate the functional link between cocaine and p38 MAPK/MSK1 pathways. Together, our results demonstrate for the first time that the p38 MAPK/MSK1 signaling pathway plays a critical role in the cocaine-induced potentiating effects on HIV-1 infection, thus providing new insights into the interplay between cocaine abuse and HIV-1 neuro-pathogenesis. [ABSTRACT FROM AUTHOR]
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- 2016
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5. Impact of cocaine abuse on HIV pathogenesis.
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Dash, Sabyasachi, Balasubramaniam, Muthukumar, Villalta, Fernando, Dash, Chandravanu, Pandhare, Jui, Chandel, Nirupama, Shama, Prem L., and George, Varghese
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HIV infections ,COCAINE abuse ,PUBLIC health - Abstract
Over 1.2 million people in the United States are infected with the human immunodeficiency virus type 1 (HIV-1). Tremendous progress has been made over the past three decades on many fronts in the prevention and treatment of HIV-1 disease. However, HIV-1 infection is incurable and antiretroviral drugs continue to remain the only effective treatment option for HIV infected patients. Unfortunately, only three out of ten HIV-1 infected individuals in the US have the virus under control. Thus, majority of HIV-1 infected individuals in the US are either unaware of their infection status or not connected/retained to care or are non-adherent to antiretroviral therapy (ART). This national public health crisis, as well as the ongoing global HIV/AIDS pandemic, is further exacerbated by substance abuse, which serves as a powerful cofactor at every stage of HIV/AIDS including transmission, diagnosis, pathogenesis, and treatment. Clinical studies indicate that substance abuse may increase viral load, accelerate disease progression and worsen AIDS-related mortality even among ART-adherent patients. However, confirming a direct causal link between substance abuse and HIV/AIDS in human patients remains a highly challenging endeavor. In this review we will discuss the recent and past developments in clinical and basic science research on the effects of cocaine abuse on HIV-1 pathogenesis. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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6. Inhibition of multi-drug resistant HIV-1 reverse transcriptase by nucleoside β-triphosphates
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Dash, Chandravanu, Ahmadibeni, Yousef, Hanley, Michael J., Pandhare, Jui, Gotte, Mathias, Le Grice, Stuart F.J., and Parang, Keykavous
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MULTIDRUG resistance , *NUCLEOSIDE reverse transcriptase inhibitors , *DINUCLEOSIDE polyphosphates , *HIV infections , *DRUG development , *ANTIRETROVIRAL agents , *THYMIDINE , *ENZYME activation , *SOLID-phase synthesis , *DNA polymerases - Abstract
Abstract: Despite the success of potent reverse transcriptase (RT) inhibitors against human immunodeficiency virus type 1 (HIV-1) in combination regimens, the development of drug resistant RTs constitutes a major hurdle for the long-term efficacy of current antiretroviral therapy. Nucleoside β-triphosphate analogs of adenosine and nucleoside reverse transcriptase inhibitors (NRTIs) (3′-azido-2′,3′-dideoxythymidine (AZT), 3′-fluoro-2′,3′-dideoxythymidine (FLT), and 2′,3′-didehydro-2′,3′-dideoxythymidine (d4T)) were synthesized and their inhibitory activities were evaluated against wild-type and multidrug resistant HIV-1 RTs. Adenosine β-triphosphate (1) and AZT β-triphosphate (2) completely inhibited the DNA polymerase activity of wild type, the NRTI multi resistant, and nonnucleoside RT inhibitors (NNRTI) resistant HIV-1 RT at 10nM, 10 and 100μM, respectively. [Copyright &y& Elsevier]
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- 2011
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7. A prospective on drug abuse-associated epigenetics and HIV-1 replication
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Pandhare, Jui and Dash, Chandravanu
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PHYSIOLOGICAL effects of drug abuse? , *HIV infections , *DISEASE susceptibility , *MOLECULAR structure , *LIFE cycles (Biology) , *VIRAL replication , *AIDS - Abstract
Abstract: Drugs of abuse serve as cofactors to susceptibility to HIV infection and disease progression. Although clinical reports indicate association between HIV/AIDS and drug use, the molecular mechanism of infection susceptibility and disease progression remains unclear. Drugs such as cocaine exert their addictive effects in part by epigenetic mechanisms. Given that epigenetic modifications play an important role in HIV-1 life cycle, it is essential to unravel whether drug abuse-associated epigenetic changes may contribute to HIV/AIDS. In this article we will provide a prospective on the impact of epigenetic mechanisms on HIV-1 life cycle. [Copyright &y& Elsevier]
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- 2011
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8. Solid-phase synthesis of 5′-O-β,γ-methylenetriphosphate derivatives of nucleosides and evaluation of their inhibitory activity against HIV-1 reverse transcriptase
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Ahmadibeni, Yousef, Dash, Chandravanu, Le Grice, Stuart F.J., and Parang, Keykavous
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SOLID-phase synthesis , *PHOSPHATES , *NUCLEOSIDES , *HIV , *REVERSE transcriptase , *METHANE , *CHEMICAL reagents , *GUMS & resins - Abstract
Abstract: Bis(dichlorophosphino)methane was converted to a β,γ-methylenetriphosphitylating reagent. The reagent was immobilized on aminomethyl polystyrene resin-bound linker of 4-acetoxy-3-phenylbenzyl alcohol to afford a polymer-bound β,γ-methylenetriphosphitylating reagent, which was reacted with unprotected nucleosides followed by oxidation with tert-butyl hydroperoxide, deprotection of cyanoethoxy groups with DBU, and acidic cleavage to produce 5′-O-β,γ-methylene triphosphate nucleosides in 53–82% overall yields. Among all the compounds, cytidine 5′-O-β,γ-methylenetriphosphate inhibited completely RNase H activity of HIV-1 reverse transcriptase at 700μM. [Copyright &y& Elsevier]
- Published
- 2010
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9. Examining Interactions of HIV-1 Reverse Transcriptase with Single-stranded Template Nucleotides by Nucleoside Analog Interference.
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Dash, Chandravanu, Fisher, Timothy S., Prasad, Vinayaka R., and Le Grice, Stuart F. J.
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HIV , *DNA polymerases , *NUCLEOSIDES , *ENZYMES , *GENES , *NUCLEOTIDES - Abstract
Crystallographic studies have implicated several residues of the p66 fingers subdomain of human immunodeficiency virus type-1 reverse transcriptase in contacting the single-stranded template overhang immediately ahead of the DNA polymerase catalytic center. This interaction presumably assists in inducing the appropriate geometry on the template base for efficient and accurate incorporation of the incoming dNTP, To investigate this, we introduced nucleoside analogs either individually or in tandem into the DNA template ahead of the catalytic center and investigated whether they induce pausing of the replication machinery before serving as the template base. Analogs included abasic tetrahydrofuran linkages, neutralizing methylphosphonate linkages, and conformationally locked nucleosides. In addition, several Phe-61 mutants were included in our analysis, based on previous data indicating that altering this residue affects both strand displacement synthesis and the fidelity of DNA synthesis. We demonstrate here that altering the topology of the template strand two nucleotides ahead of the catalytic center can interrupt DNA synthesis. Mutating Phe-61 to either Ala or Leu accentuates this defect, whereas replacement with an aromatic residue (Trp) allows the mutant enzyme to bypass the template analogs with relative ease. [ABSTRACT FROM AUTHOR]
- Published
- 2006
- Full Text
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10. Two Modes of HIV-1 Polypurine Tract Cleavage Are Affected by Introducing Locked Nucleic Acid Analogs into the (-) DNA Template.
- Author
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Dash, Chandravanu, Hye-Young Yi-Brunozzi, and Le Grice, Stuart F. J.
- Subjects
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HIV , *REVERSE transcriptase , *NUCLEIC acids , *RIBONUCLEASES , *RNA , *DNA - Abstract
Unusual base-pairing in a co-crystal of reverse transcriptase (RT) and a human immunodeficiency virus type 1 (HIV-1) polypurine tract (PPT)-containing RNA/ DNA hybrid suggests local nucleic acid flexibility mediates selection of the plus-strand primer. Structural elements of HIV-1 RT potentially participating in recognition of this duplex include the thumb subdomain and the ribonuclease H (RNase H) primer grip, the latter comprising elements of the connection subdomain and RNase H domain. To investigate how stabilizing HIV-1 PPT structure influences its recognition, we modified the (-) DNA template by inserting overlapping locked nucleic acid (LNA) doublets and triplets. Modified RNA/ DNA hybrids were evaluated for cleavage at the PPT/U3 junction. Altered specificity was observed when the homopolymeric dA·rU tract immediately 5′ of the PPT was modified, whereas PPT/U3 cleavage was lost after substitutions in the adjacent dT·rA tract. In contrast, the ‘unzipped’ portion of the PPT was moderately insensitive to LNA insertions. Although a portion of the dC·rG and neighboring dT·rA tract were minimally affected by LNA insertion, RNase H activity was highly sensitive to altering the junction between these structural elements. Using 3′-end-labeled PPT RNA primers, we also identified novel cleavage sites ahead (+5/+6) of the PPT/U3 junction. Differential cleavage at the PPT/U3 junction and U3 + 5/+6 site in response to LNA-induced template modification suggests two binding modes for HIV-1 RT, both of which may be controlled by the interaction of its thumb subdomain (potentially via the minor groove binding track) at either site of the unzipped region. [ABSTRACT FROM AUTHOR]
- Published
- 2004
- Full Text
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11. Correction: Cocaine Enhances HIV-1 Replication in CD4+ T Cells by Down-Regulating MiR-125b.
- Author
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Mantri, Chinmay K., Pandhare Dash, Jui, Mantri, Jyoti Velamarti, and Dash, Chandravanu
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COCAINE ,DNA replication ,HIV - Published
- 2018
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12. Emerging role of cyclophilin A in HIV-1 infection: from producer cell to the target cell nucleus.
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Padron, Adrian, Prakash, Prem, Pandhare, Jui, Luban, Jeremy, Aiken, Chris, Balasubramaniam, Muthukumar, and Dash, Chandravanu
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CELL nuclei , *HIV , *CYCLOPHILINS , *CYTOSKELETAL proteins , *KNOWLEDGE gap theory - Abstract
The HIV-1 genome encodes a small number of proteins with structural, enzymatic, regulatory, and accessory functions. These viral proteins interact with a number of host factors to promote the early and late stages of HIV-1 infection. During the early stages of infection, interactions between the viral proteins and host factors enable HIV-1 to enter the target cell, traverse the cytosol, dock at the nuclear pore, gain access to the nucleus, and integrate into the host genome. Similarly, the viral proteins recruit another set of host factors during the late stages of infection to orchestrate HIV-1 transcription, translation, assembly, and release of progeny virions. Among the host factors implicated in HIV-1 infection, Cyclophilin A (CypA) was identified as the first host factor to be packaged within HIV-1 particles. It is now well established that CypA promotes HIV-1 infection by directly binding to the viral capsid. Mechanistic models to pinpoint CypA's role have spanned from an effect in the producer cell to the early steps of infection in the target cell. In this review, we will describe our understanding of the role(s) of CypA in HIV-1 infection, highlight the current knowledge gaps, and discuss the potential role of this host factor in the post-nuclear entry steps of HIV-1 infection. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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13. The Tennessee Center for AIDS Research HIV Research Training Program for Minority High School and Undergraduate Students: Development, Implementation, and Early Outcomes.
- Author
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Koethe, John R., Eeds, Angela, Stewart, LaMonica V., Haas, David W., Hildreth, James E. K., Mallal, Simon, Wanjalla, Celestine, Perkins, Jessica, Ahonkhai, Aima, Dong, Xinhong, Berhanu, Rebecca, and Dash, Chandravanu
- Abstract
Background: The Southern region of the United States has the highest HIV incidence, and new infections disproportionately affect Black Americans. The Tennessee Center for AIDS Research (CFAR) Diversity, Equity, and Inclusion Pathway Initiative (CDEIPI) program supports the training of individuals from groups underrepresented in medicine and science in multiple areas of research to increase the pool of HIV-focused investigators at early educational and career stages. Setting: The Tennessee CFAR is a partnership between Vanderbilt University Medical Center, Meharry Medical College (one of the oldest historically Black medical colleges), Tennessee Department of Health, and Nashville Community AIDS Resources, Education and Services (a sophisticated community service organization, which emphasizes research training responsive to regional and national priorities). Methods: The Tennessee CFAR CDEIPI program leverages existing Vanderbilt University Medical Center and Meharry Medical College structured biomedical training programs for high school and undergraduate students to provide an intensive, mentored, HIV research experience augmented by CFAR resources situating this training within the broader history, scientific breadth, and societal and political aspects of the HIV epidemic. Results: The first year of the Tennessee CFAR CDEIPI program trained 3 high school and 3 undergraduate students from underrepresented in medicine and science backgrounds in basic, clinical/translational, and community-focused research projects with a diverse group of 9 mentors. All students completed the program, and evaluations yielded positive feedback regarding mentoring quality and effectiveness, and continued interest in HIVrelated research. Conclusions: The Tennessee CFAR CDEIPI program will continue to build upon experience from the first year to further contribute to national efforts to increase diversity in HIVrelated research. [ABSTRACT FROM AUTHOR]
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- 2023
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14. HIV-1 Preintegration Complex Preferentially Integrates the Viral DNA into Nucleosomes Containing Trimethylated Histone 3-Lysine 36 Modification and Flanking Linker DNA.
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Sapp, Nicklas, Burge, Nathaniel, Cox, Khan, Prakash, Prem, Balasubramaniam, Muthukumar, Thapa, Santosh, Christensen, Devin, Min Li, Linderberger, Jared, Kvaratskhelia, Mamuka, Pandhare, Jui, Craigie, Robert, Poirier, Michael G., and Dash, Chandravanu
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CHROMATIN , *HISTONES , *VIRAL DNA , *DNA condensation , *DNA , *HUMAN chromatin , *HIV - Abstract
HIV-1 DNA is preferentially integrated into chromosomal hot spots by the preintegration complex (PIC). To understand the mechanism, we measured the DNA integration activity of PICs--extracted from infected cells--and intasomes, biochemically assembled PIC substructures using a number of relevant target substrates. We ob-served that PIC-mediated integration into human chromatin is preferred compared to genomic DNA. Surprisingly, nucleosomes lacking histone modifications were not preferred integration compared to the analogous naked DNA. Nucleosomes containing the trimethylated histone 3 lysine 36 (H3K36me3), an epigenetic mark linked to active transcription, significantly stimulated integration, but the levels remained lower than the naked DNA. Notably, H3K36me3-modified nucleosomes with linker DNA optimally supported integration mediated by the PIC but not by the intasome. Interestingly, optimal intasome-mediated integration required the cellular cofactor LEDGF. Unexpectedly, LEDGF minimally affected PIC-mediated integration into naked DNA but blocked integration into nucleosomes. The block for the PIC-mediated integration was significantly relieved by H3K36me3 modification. Mapping the integration sites in the preferred substrates revealed that specific features of the nucleosome-bound DNA are preferred for integration, whereas integration into naked DNA was random. Finally, biochemical and genetic studies demonstrate that DNA condensation by the H1 protein dramatically reduces integration, providing further evidence that features inherent to the open chromatin are preferred for HIV-1 integration. Collectively, these results identify the optimal target substrate for HIV-1 integration, report a mechanistic link between H3K36me3 and integration preference, and importantly, reveal distinct mechanisms utilized by the PIC for integration compared to the intasomes. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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15. Human Three Prime Repair Exonuclease 1 Promotes HIV-1 Integration by Preferentially Degrading Unprocessed Viral DNA.
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Davids, Benem-Orom, Balasubramaniam, Muthukumar, Sapp, Nicklas, Prakash, Prem, Ingram, Shalonda, Min Li, Craigie, Robert, Hollis, Thomas, Pandhare, Jui, and Dash, Chandravanu
- Subjects
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HIV , *EXONUCLEASES , *VIRAL DNA , *DNA viruses - Abstract
Three prime repair exonuclease 1 (TREX1) is the most abundant 39!59 exonuclease in mammalian cells. It has been suggested that TREX1 degrades HIV-1 DNA to enable the virus to evade the innate immune system. However, the exact role of TREX1 during early steps of HIV-1 infection is not clearly understood. In this study, we report that HIV-1 infection is associated with upregulation, perinuclear accumulation, and nuclear localization of TREX1. However, TREX1 overexpression did not affect reverse transcription or nuclear entry of the virus. Surprisingly, HIV-1 DNA integration was increased in TREX1-overexpressing cells, suggesting a role of the exonuclease in the post-nuclear entry step of infection. Accordingly, preintegration complexes (PICs) extracted from TREX1-overexpressing cells retained higher levels of DNA integration activity. TREX1 depletion resulted in reduced levels of proviral integration, and PICs formed in TREX1-depleted cells retained lower DNA integration activity. Addition of purified TREX1 to PICs also enhanced DNA integration activity, suggesting that TREX1 promotes HIV-1 integration by stimulating PIC activity. To understand the mechanism, we measured TREX1 exonuclease activity on substrates containing viral DNA ends. These studies revealed that TREX1 preferentially degrades the unprocessed viral DNA, but the integration-competent 39-processed viral DNA remains resistant to degradation. Finally, we observed that TREX1 addition stimulates the activity of HIV-1 intasomes assembled with the unprocessed viral DNA but not that of intasomes containing the 39-processed viral DNA. These biochemical analyses provide a mechanism by which TREX1 directly promotes HIV-1 integration. Collectively, our study demonstrates that HIV-1 infection upregulates TREX1 to facilitate viral DNA integration. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
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16. A Novel Role of Proline Oxidase in HIV-1 Envelope Glycoprotein-induced Neuronal Autophagy.
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Pandhare, Jui, Dash, Sabyasachi, Jones, Bobby, Villalta, Fernando, and Dash, Chandravanu
- Subjects
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PROLINE , *AUTOPHAGY , *CARBOXYLATES , *REACTIVE oxygen species , *HIV , *APOPTOSIS - Abstract
Proline oxidase (POX) catalytically converts proline to pyrroline-5-carboxylate. This catabolic conversion generates reactive oxygen species (ROS) that triggers cellular signaling cascades including autophagy and apoptosis. This study for the first time demonstrates a role of POX in HIV-1 envelope glycoprotein (gp120)-induced neuronal autophagy. HIV-1 gp120 is a neurotoxic factor and is involved in HIV-1-associated neurological disorders. However, the mechanism of gp120-mediated neurotoxicity remains unclear. Using SH-SY5Y neuroblastoma cells as a model, this study demonstrates that gp120 treatment induced POX expression and catalytic activity. Concurrently, gp120 also increased intracellular ROS levels. However, increased ROS had a minimal effect on neuronal apoptosis. Further investigation indicated that the immediate cellular response to increased ROS paralleled with induction of autophagy markers, beclin-1 and LC3-II. These data lead to the hypothesis that neuronal autophagy is activated as a cellular protective response to the toxic effects of gp120. A direct and functional role of POX in gp120-mediated neuronal autophagy was examined by inhibition and overexpression studies. Inhibition of POX activity by a competitive inhibitor "dehydroproline" decreased ROS levels concomitant with reduced neuronal autophagy. Conversely, overexpression of POXin neuronal cells increased ROS levels and activated ROS-dependent autophagy. Mechanistic studies suggest that gp120 induces POX by targeting p53. Luciferase reporter assays confirm that p53 drives POX transcription. Furthermore, data demonstrate that gp120 induces p53 via binding to the CXCR4 co-receptor. Collectively, these results demonstrate a novel role of POX as a stress response metabolic regulator in HIV-1 gp120-associated neuronal autophagy. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
17. Mutations M184V and Y115F in HIV-1 Reverse Transcriptase Discriminate against "Nucleotide-competing Reverse Transcriptase Inhibitors".
- Author
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Ehteshami, Maryam, Scarth, Brian J., Tchesnokov, Egor P., Dash, Chandravanu, Le Grice, Stuart F. J., Hallenberger, Sabine, Jochmans, Dirk, and Götte, Matthias
- Subjects
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REVERSE transcriptase , *TRANSCRIPTION factors , *HIV , *DNA polymerases , *IMMUNODEFICIENCY - Abstract
Indolopyridones are potent inhibitors of reverse transcriptase (RT) of the human immunodeficiency virus type 1 (HIV-1). Although the structure of these compounds differs from established nucleoside analogue RT inhibitors (NRTIs), previous studies suggest that the prototype compound INDOPY-1 may bind in close proximity to the polymerase active site. NRTIassociated mutations that are clustered around the active site confer decreased, e.g. M184V and Y115F, or increased, e.g. K65R, susceptibility to INDOPY-1. Here we have studied the underlying biochemical mechanism. RT enzymes containing the isolated mutations M184V and Y115F cause 2-3-fold increases in IC50 values, while the combination of the two mutations causes a >15-fold increase. K65R can partially counteract these effects. Binding studies revealed that the M184V change reduces the affinity to INDOPY-1, while Y115F facilitates binding of the natural nucleotide substrate and the combined effects enhance the ability of the enzyme to discriminate against the inhibitor. Studies with other strategic mutations at residues Phe-61 and Ala-62, as well as the use of chemically modified templates shed further light on the putative binding site of the inhibitor and ternary complex formation. An abasic site residue at position n, i.e. opposite the 3′-end of the primer, prevents binding of INDOPY-1, while an abasic site at the adjacent position n+1 has no effect. Collectively, our findings provide strong evidence to suggest that INDOPY-1 can compete with natural deoxynucleoside triphosphates (dNTPs). We therefore propose to refer to members of this class of compounds as "nucleotide-competing RT inhibitors" (NcRTIs). [ABSTRACT FROM AUTHOR]
- Published
- 2008
- Full Text
- View/download PDF
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