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https://www.readbyqxmd.com/read/29792216/hiv-1-tat-phosphorylation-on-ser-16-residue-modulates-hiv-1-transcription
#1
Andrey Ivanov, Xionghao Lin, Tatiana Ammosova, Andrey V Ilatovskiy, Namita Kumari, Hatajai Lassiter, Nowah Afangbedji, Xiaomei Niu, Michael G Petukhov, Sergei Nekhai
BACKGROUND: HIV-1 transcription activator protein Tat is phosphorylated in vitro by CDK2 and DNA-PK on Ser-16 residue and by PKR on Tat Ser-46 residue. Here we analyzed Tat phosphorylation in cultured cells and its functionality. RESULTS: Mass spectrometry analysis showed primarily Tat Ser-16 phosphorylation in cultured cells. In vitro, CDK2/cyclin E predominantly phosphorylated Tat Ser-16 and PKR-Tat Ser-46. Alanine mutations of either Ser-16 or Ser-46 decreased overall Tat phosphorylation...
May 23, 2018: Retrovirology
https://www.readbyqxmd.com/read/29787233/controlling-the-replication-of-a-genomically-recoded-hiv-1-with-a-functional-quadruplet-codon-in-mammalian-cells
#2
Yan Chen, Yanmin Wan, Nanxi Wang, Zhe Yuan, Wei Niu, Qingsheng Li, Jiantao Guo
Large efforts have been devoted to the genetic code engineering in the past decade, aiming for unnatural amino acid mutagenesis. Recently, an increasing number of studies were reported to employ quadruplet codons to encode unnatural amino acids. We and others have demonstrated that the quadruplet decoding efficiency could be significantly enhanced by an extensive engineering of tRNAs bearing an extra nucleotide in their anticodon loops. In this work, we report the identification of tRNA mutants derived from directed evolution to efficiently decode a UAGA quadruplet codon in mammalian cells...
May 22, 2018: ACS Synthetic Biology
https://www.readbyqxmd.com/read/29780163/heteromerization-of-%C3%AE-opioid-receptor-and-cholecystokinin-b-receptor-through-the-third-transmembrane-domain-of-the-%C3%AE-opioid-receptor-contributes-to-the-anti-opioid-effects-of-cholecystokinin-octapeptide
#3
Yin Yang, Qian Li, Qi-Hua He, Ji-Sheng Han, Li Su, You Wan
Activation of the cholecystokinin type B receptor (CCKBR) by cholecystokinin octapeptide (CCK-8) inhibits opioid analgesia. Chronic opiate treatment leads to an increase in the CCK-8 concentration and thus enhances the antagonism of CCK-8 against opioid analgesia; the underlying molecular mechanisms remain of great interest. In the present study, we validated the colocalization of the μ-opioid receptor (MOR) and CCKBR in pain signal transmission-related spinal cord dorsal horn and dorsal root ganglion neurons of rats...
May 21, 2018: Experimental & Molecular Medicine
https://www.readbyqxmd.com/read/29775947/hit-optimization-studies-of-3-hydroxy-indolin-2-one-analogs-as-potential-anti-hiv-1-agents
#4
Subhash Chander, Cheng-Run Tang, Ashok Penta, Ping Wang, Deepak P Bhagwat, Nicolas Vanthuyne, Muriel Albalat, Payal Patel, Sanskruti Sankpal, Yong-Tang Zheng, Murugesan Sankaranarayanan
In the current study, twenty-two compounds based upon 3-hydroxy-3-(2-oxo-2-phenylethyl)indolin-2-one nucleus were designed, synthesized and in vitro evaluated for HIV-1 RT inhibition and anti-HIV-1 activity. Compounds 3d, 5c and 5e demonstrated encouraging potency against RT enzyme as well as HIV-1 in low micromolar to nanomolar concentration with good to excellent safety index. Structure activity relationship studies revealed that halogens such as bromo or chloro at 5th the position of oxindole ring remarkably enhanced the potency against RT...
May 9, 2018: Bioorganic Chemistry
https://www.readbyqxmd.com/read/29769116/efficacies-of-cabotegravir-and-bictegravir-against-drug-resistant-hiv-1-integrase-mutants
#5
Steven J Smith, Xue Zhi Zhao, Terrence R Burke, Stephen H Hughes
BACKGROUND: Integrase strand transfer inhibitors (INSTIs) are the class of antiretroviral (ARV) drugs most recently approved by the FDA for the treatment of HIV-1 infections. INSTIs block the strand transfer reaction catalyzed by HIV-1 integrase (IN) and have been shown to potently inhibit infection by wild-type HIV-1. Of the three current FDA-approved INSTIs, Dolutegravir (DTG), has been the most effective, in part because treatment does not readily select for resistant mutants. However, recent studies showed that when INSTI-experienced patients are put on a DTG-salvage therapy, they have reduced response rates...
May 16, 2018: Retrovirology
https://www.readbyqxmd.com/read/29753024/chemical-system-biology-based-molecular-interactions-to-identify-inhibitors-against-q151m-mutant-of-hiv-1-reverse-transcriptase
#6
Rajan Kumar Pandey, Drista Sharma, Rupal Ojha, Tarun Kumar Bhatt, Vijay Kumar Prajapati
The emergence of mutations leading to drug resistance is the main cause of therapeutic failure in the human HIV infection. Chemical system biology approach has drawn great attention to discover new antiretroviral hits with high efficacy and negligible toxicity, which can be used as a prerequisite for HIV drug resistance global action plan 2017-21. To discover potential hits, we docked 49 antiretroviral analogs (n = 6294) against HIV-1 reverse transcriptase Q151M mutant & its wild-type form and narrow downed their number in three sequential modes of docking using Schrödinger suite...
May 9, 2018: Infection, Genetics and Evolution
https://www.readbyqxmd.com/read/29752967/hiv-1-matrix-protein-interactions-with-trna-implications-for-membrane-targeting
#7
Christy R Gaines, Emre Tkacik, Amalia Rivera-Oven, Phoebe Somani, Alecia Achimovich, Tawakalitou Alabi, Angela Zhu, Noel Getachew, Ae Lim Yang, Matthew McDonough, Tarik Hawkins, Zoe Spadaro, Michael F Summers
The N-terminally myristoylated matrix domain (MA) of the HIV-1 Gag polyprotein promotes virus assembly by targeting Gag to the inner leaflet of the plasma membrane (PM). Recent studies indicate that, prior to membrane binding, MA associates with cytoplasmic tRNAs (including tRNALys3 ), and in vitro studies of tRNA-dependent MA interactions with model membranes have led to proposals that competitive tRNA interactions contribute to membrane discrimination. We have characterized interactions between native, mutant, and unmyristylated (myr-) MA proteins and recombinant tRNALys3 by NMR spectroscopy and isothermal titration calorimetry (ITC)...
May 9, 2018: Journal of Molecular Biology
https://www.readbyqxmd.com/read/29751762/hiv-latency-reversing-agents-act-through-tat-post-translational-modifications
#8
Georges Khoury, Talia M Mota, Shuang Li, Carolin Tumpach, Michelle Y Lee, Jonathan Jacobson, Leigh Harty, Jenny L Anderson, Sharon R Lewin, Damian F J Purcell
BACKGROUND: Different classes of latency reversing agents (LRAs) are being evaluated to measure their effects in reactivating HIV replication from latently infected cells. A limited number of studies have demonstrated additive effects of LRAs with the viral protein Tat in initiating transcription, but less is known about how LRAs interact with Tat, particularly through basic residues that may be post-translationally modified to alter the behaviour of Tat for processive transcription and co-transcriptional RNA processing...
May 11, 2018: Retrovirology
https://www.readbyqxmd.com/read/29743377/equine-myxovirus-resistance-protein-2-restricts-lentiviral-replication-by-blocking-nuclear-uptake-of-capsid-protein
#9
Shuang Ji, Lei Na, Huiling Ren, Yujie Wang, Xiaojun Wang
Human Myxovirus resistance 2 (huMxB) has been shown to be a determinant type I interferon-induced host factor involved in the inhibition of HIV-1 as well as many other primate lentiviruses. This blocking occurs after the reverse transcription of viral RNA and ahead of the integration into the host DNA, which is closely connected to the ability of the protein to bind the viral capsid. To date, Mx2s derived from non-primate animals have shown no capacity for HIV-1 suppression. In this study, we examined the restrictive effect of equine Mx2 (eqMx2) on both the equine infectious anemia virus (EIAV) and HIV-1 and investigated possible mechanisms for its specific function...
May 9, 2018: Journal of Virology
https://www.readbyqxmd.com/read/29743079/hiv-1-tat-expression-and-sulphamethoxazole-hydroxylamine-mediated-oxidative-stress-alter-the-disulfide-proteome-in-jurkat-t-cells
#10
Kemi Adeyanju, John R Bend, Michael J Rieder, Gregory A Dekaban
BACKGROUND: Adverse drug reactions (ADRs) are a significant problem for HIV patients, with the risk of developing ADRs increasing as the infection progresses to AIDS. However, the pathophysiology underlying ADRs remains unknown. Sulphamethoxazole (SMX) via its active metabolite SMX-hydroxlyamine, when used prophylactically for pneumocystis pneumonia in HIV-positive individuals, is responsible for a high incidence of ADRs. We previously demonstrated that the HIV infection and, more specifically, that the HIV-1 Tat protein can exacerbate SMX-HA-mediated ADRs...
May 9, 2018: Virology Journal
https://www.readbyqxmd.com/read/29737220/emerging-reverse-transcriptase-inhibitors-for-hiv-1-infection
#11
Mohammad A Rai, Sam Pannek, Carl J Fichtenbaum
There are 36.7 million people living with HIV with 20.9 million having access to antiretroviral therapy (ART). Nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) remain the 'backbone' of ART. However, the currently available nine NRTIs and five non-nucleoside reverse transcriptase inhibitors (NNRTIs) have significant side effects and resistance profiles. Areas covered: We summarize the mechanisms of resistance and other limitations of the existing NRTIs/NNRTIs. GS-9131, MK-8591, Elsulfavirine and Doravirine are four new agents that are furthest along in development...
May 8, 2018: Expert Opinion on Emerging Drugs
https://www.readbyqxmd.com/read/29734365/nod2-is-required-for-antigen-specific-humoral-responses-against-antigens-orally-delivered-using-a-recombinant-lactobacillus-vaccine-platform
#12
Sara A Bumgardner, Lin Zhang, Alora S LaVoy, Barbara Andre, Chad B Frank, Akinobu Kajikawa, Todd R Klaenhammer, Gregg A Dean
Safe and efficacious orally-delivered mucosal vaccine platforms are desperately needed to combat the plethora of mucosally transmitted pathogens. Lactobacillus spp. have emerged as attractive candidates to meet this need and are known to activate the host innate immune response in a species- and strain-specific manner. For selected bacterial isolates and mutants, we investigated the role of key innate immune pathways required for induction of innate and subsequent adaptive immune responses. Co-culture of murine macrophages with L...
2018: PloS One
https://www.readbyqxmd.com/read/29732900/%C3%AE-1-6-fucosylated-complex-glycan-binding-lentil-lectin-enhances-in-vitro-hiv-1-infection-and-dc-sign-mediated-viral-capture-and-transmission-to-cd4-cells
#13
Muzafar Jan, Shallu Tomer, Sunil K Arora
This study was designated to study the effect of glycan composition on lectin-mediated inhibition of HIV-1 infection and transmission. We found that Lens culinaris agglutinin (LCA), an α(1-6)-fucosylated complex glycan-binding lectin, remarkably enhances the susceptibility of cells for HIV-1 infection and DC-SIGN-mediated capture and transmission. The role of glycan involvement was studied by using glycan-modified viruses produced in the presence of glycosidase inhibitors and mutant cell lines. The data suggests that the LCA-mediated enhancement in viral infection and trans-infection was not determined by the glycan composition of virus...
May 6, 2018: AIDS Research and Human Retroviruses
https://www.readbyqxmd.com/read/29718409/the-puzzle-of-hiv-neutral-and-selective-evolution
#14
Thomas Leitner
HIV is one of the fastest evolving organisms known. It evolves about 1 million times faster than its host, humans. Because HIV establishes chronic infections, with continuous evolution, its divergence within a single infected human surpasses the divergence of the entire humanoid history. Yet, it is still the same virus, infecting the same cell types and using the same replication machinery year after year. Hence, one would think that most mutations that HIV accumulates are neutral. But the picture is more complicated than that...
April 27, 2018: Molecular Biology and Evolution
https://www.readbyqxmd.com/read/29707588/development-of-safe-and-non-self-immunogenic-mucosal-adjuvant-by-recombinant-fusion-of-cholera-toxin-a1-subunit-with-protein-transduction-domain
#15
Byoung-Shik Shim, In Su Cheon, Eugene Lee, Sung-Moo Park, Youngjoo Choi, Dae-Im Jung, Eunji Yang, Jung-Ah Choi, June Young Chun, Jae-Ouk Kim, Cheol-Heui Yun, Cecil Czerkinsky, Man Ki Song
Potential use of cholera toxin (CT) as a mucosal vaccine adjuvant has been documented in a variety of animal models. However, native CT is highly toxic to be used as a mucosal adjuvant in humans. Here, we demonstrate a new approach to generate a mucosal adjuvant by replacing the B subunit of CT with HIV-1 Tat protein transduction domain (PTD), which efficiently delivers fusion proteins into the cell cytoplasm by unspecific binding to cell surface. We compared the adjuvanticity and toxicity of Tat PTD-CTA1-Tat PTD (TCTA1T) with those of CT...
2018: Journal of Immunology Research
https://www.readbyqxmd.com/read/29699924/design-synthesis-and-biological-evaluation-of-substituted-sg-1-derivatives-as-novel-anti-hiv-agents
#16
Xiaoyu Liu, Panpan Chen, Xiaoyu Li, Mingyu Ba, Xiaozhen Jiao, Ying Guo, Ping Xie
SG-1 was previously identified as a potent Non-nucleoside reverse transcriptase inhibitors (NNRTI) which works through inhibition of reverse transcriptase (RT) RNA-dependent DNA polymerase activity via a direct binding event. To further investigate the relationship between its structure and activity, four series of novel analogues were designed and synthesized with 12 of them inhibiting HIV-1 replication with IC50 s in the range 0.09-6.71 μM. Compound 4b, 4c, 4f, 2 and 6b were further tested on two NNRTI-resistant HIV-1 strains and one NNRTI-resistant superbug...
April 20, 2018: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29695435/critical-role-of-the-htlv-1-capsid-n-terminal-domain-for-gag-gag-interactions-and-virus-particle-assembly
#17
Jessica L Martin, Luiza Mendonça, Rachel Marusinec, Jennifer Zuczek, Isaac Angert, Ruth J Blower, Joachim D Mueller, Juan R Perilla, Wei Zhang, Louis M Mansky
The retroviral Gag protein is the main structural protein responsible for virus particle assembly and release. Like human immunodeficiency virus type 1 (HIV-1) Gag, human T-cell leukemia virus type 1 (HTLV-1) has a structurally conserved capsid (CA) domain, including a β-hairpin turn and a centralized coiled-coil-like structure of six α helices in the CA amino-terminal domain (NTD) as well as four α-helices in the CA carboxy-terminal domain (CTD). CA drives Gag oligomerization, which is critical for both immature Gag lattice formation and particle production...
April 25, 2018: Journal of Virology
https://www.readbyqxmd.com/read/29677136/cytoplasmic-translocation-of-nucleolar-protein-nop53-promotes-viral-replication-by-suppressing-host-defense
#18
Wen Meng, Shi-Chong Han, Cui-Cui Li, Hui-Jun Dong, Jian-Yu Chang, Hwa-Chain Robert Wang, Xiao-Jia Wang
NOP53 is a tumor suppressor protein located in the nucleolus and is translocated to the cytoplasm during infection by vesicular stomatitis virus (VSV) and herpes simplex virus type 1 (HSV-1), as shown in our previous study. Cytoplasmic NOP53 interacts with the retinoic acid-inducible gene I (RIG-I) to remove its K63-linked ubiquitination, leading to attenuation of type I interferon IFN-β. In the present study, we found no obvious translocation of NOP53 in infection by a mutant virus lacking ICP4 (HSV-1/d120, replication inadequate)...
April 20, 2018: Viruses
https://www.readbyqxmd.com/read/29670696/discovery-of-novel-diarylpyrimidine-derivatives-as-potent-hiv-1-nnrtis-targeting-the-nnrti-adjacent-binding-site
#19
Zhipeng Huo, Heng Zhang, Dongwei Kang, Zhongxia Zhou, Gaochan Wu, Samuel Desta, Xiaofang Zuo, Zhao Wang, Lanlan Jing, Xiao Ding, Dirk Daelemans, Erik De Clercq, Christophe Pannecouque, Peng Zhan, Xinyong Liu
A novel series of diarylpyrimidine derivatives, which could simultaneously occupy the classical NNRTIs binding pocket (NNIBP) and the newly reported "NNRTI Adjacent" binding site, were designed, synthesized, and evaluated for their antiviral activities in MT-4 cell cultures. The results demonstrated that six compounds ( 20 , 27 and 31 - 34 ) showed excellent activities against wild-type (WT) HIV-1 strain (EC50 = 2.4-3.8 nM), which were more potent than that of ETV (EC50 = 4.0 nM). Furthermore, 20 , 27 , 33 , and 34 showed more potent or equipotent activity against single mutant HIV-1 strains compared to that of ETV...
April 12, 2018: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29664566/generation-of-memory-b-cells-and-their-reactivation
#20
REVIEW
Takeshi Inoue, Imogen Moran, Ryo Shinnakasu, Tri Giang Phan, Tomohiro Kurosaki
The successful establishment of humoral memory response depends on at least two layers of defense. Pre-existing protective antibodies secreted by long-lived plasma cells act as a first line of defense against reinfection ("constitutive humoral memory"). Previously, a second line of defense in which pathogen-experienced memory B cells are rapidly reactivated to produce antibodies ("reactive humoral memory"), was considered as simply a back-up system for the first line (particularly for re-infection with homologous viruses)...
May 2018: Immunological Reviews
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