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https://www.readbyqxmd.com/read/28338924/a-nonsynonymous-snp-catalog-of-mycobacterium-tuberculosis-virulence-genes-and-its-use-for-detecting-new-potentially-virulent-sublineages
#1
N E Mikheecheva, M V Zaychikova, A V Melerzanov, V N Danilenko
Mycobacterium tuberculosis is divided into several distinct lineages, and various genetic markers such as IS-elements, VNTR, and SNPs are used for lineage identification. We propose an M. tuberculosis classification approach based on functional polymorphisms in virulence genes. An M. tuberculosis virulence genes catalog has been established, including 319 genes from various protein groups, such as proteases, cell wall proteins, fatty acid and lipid metabolism proteins, sigma factors, toxin-antitoxin systems...
March 11, 2017: Genome Biology and Evolution
https://www.readbyqxmd.com/read/28336404/mapping-region-of-human-restriction-factor-apobec3h-critical-for-interaction-with-hiv-1-vif
#2
Masaaki Nakashima, Shinya Tsuzuki, Hiroaki Awazu, Akiko Hamano, Ayaka Okada, Hirotaka Ode, Masami Maejima, Atsuko Hachiya, Yoshiyuki Yokomaku, Nobuhisa Watanabe, Hirofumi Akari, Yasumasa Iwatani
The APOBEC3 (A3) family of cellular cytidine deaminases comprises seven members (A, B, C, D, F, G, and H) that potently inhibit retroviral replication. Human immunodeficiency virus type 1 (HIV-1) Vif is a small pleiotropic protein that specifically inactivates these enzymes, targeting them for ubiquitin-mediated proteasomal degradation. A3 Vif-interaction sites are presumed to fall into three distinct types: A3C/D/F, A3G, and A3H. To date, two types of A3G and A3C/D/F sites have been well characterized, whereas the A3H Vif-binding site remains poorly defined...
March 20, 2017: Journal of Molecular Biology
https://www.readbyqxmd.com/read/28333133/fidelity-of-classwide-resistant-hiv-2-reverse-transcriptase-and-differential-contribution-of-k65r-to-the-accuracy-of-hiv-1-and-hiv-2-reverse-transcriptases
#3
Mar Álvarez, Alba Sebastián-Martín, Guillermo García-Marquina, Luis Menéndez-Arias
Nucleoside reverse transcriptase (RT) inhibitors constitute the backbone of current therapies against human immunodeficiency virus type 1 and type 2 (HIV-1 and HIV-2, respectively). However, mutational pathways leading to the development of nucleoside analogue resistance are different in both types of HIV. In HIV-2, resistance to all approved nucleoside analogues is conferred by the combination of RT substitutions K65R, Q151M and M184V. Nucleotide incorporation kinetic analyses of mutant and wild-type (WT) HIV-2 RTs show that the triple-mutant has decreased catalytic efficiency due to the presence of M184V...
March 23, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28321930/uncovering-allostery-and-regulation-in-samhd1-through-molecular-dynamics-simulations
#4
Kajwal Kumar Patra, Akash Bhattacharya, Swati Bhattacharya
The human sterile alpha motif and HD domain-containing protein 1 (SAMHD1) is a retroviral restriction factor in myeloid cells and non-cycling CD4+ T cells, a feature imputed to its phosphohydrolase activity - the enzyme depletes the cellular dNTP levels inhibiting reverse transcription. The functionally active form of SAMHD1 is an allosterically triggered tetramer which utilizes GTP-Mg(+2) -dNTP cross bridges to link and stabilize adjacent monomers. However, very little is known about how it assembles into a tetramer and how long the tetramer stays intact...
March 21, 2017: Proteins
https://www.readbyqxmd.com/read/28288662/a-mutant-tat-protein-inhibits-infection-of-human-cells-by-strains-from-diverse-hiv-1-subtypes
#5
Lina Rustanti, Hongping Jin, Mary Lor, Min Hsuan Lin, Daniel J Rawle, David Harrich
BACKGROUND: Nullbasic is a mutant HIV-1 Tat protein that inhibits HIV-1 replication via three independent mechanisms that disrupts 1) reverse transcription of the viral RNA genome into a DNA copy, 2) HIV-1 Rev protein function required for viral mRNA transport from the nucleus to the cytoplasm and 3) HIV-1 mRNA transcription by RNA Polymerase II. The Nullbasic protein is derived from the subtype B strain HIV-1BH10 and has only been tested against other HIV-1 subtype B strains. However, subtype B strains only account for ~10% of HIV-1 infections globally and HIV-1 Tat sequences vary between subtypes especially for subtype C, which is responsible for ~50% HIV-1 infection worldwide...
March 14, 2017: Virology Journal
https://www.readbyqxmd.com/read/28285916/discovery-and-optimization-of-2-pyridinone-aminal-integrase-strand-transfer-inhibitors-for-the-treatment-of-hiv
#6
John D Schreier, Mark W Embrey, Izzat T Raheem, Guillaume Barbe, Louis-Charles Campeau, David Dubost, Jamie McCabe Dunn, Jay Grobler, Timothy J Hartingh, Daria J Hazuda, Daniel Klein, Michael D Miller, Keith P Moore, Natalie Nguyen, Natasa Pajkovic, David A Powell, Vanessa Rada, John M Sanders, John Sisko, Thomas G Steele, John Wai, Abbas Walji, Min Xu, Paul J Coleman
HIV integrase strand transfer inhibitors (InSTIs) represent an important class of antiviral therapeutics with proven efficacy and excellent tolerability for the treatment of HIV infections. In 2007, Raltegravir became the first marketed strand transfer inhibitor pioneering the way to a first-line therapy for treatment-naïve patients. Challenges with this class of therapeutics remain, including frequency of the dosing regimen and the genetic barrier to resistance. To address these issues, research towards next-generation integrase inhibitors has focused on imparting potency against RAL-resistent mutants and improving pharmacokinetic profiles...
February 20, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28279801/drug-resistance-related-mutations-t369v-i-in-the-connection-subdomain-of-hiv-1-reverse-transcriptase-severely-impair-viral-fitness
#7
Zheng Wang, Junli Zhang, Fan Li, Xiaolin Ji, Lingjie Liao, Liying Ma, Hui Xing, Yi Feng, Dan Li, Yiming Shao
Fitness is a key parameter in the measurement of transmission capacity of individual drug-resistant HIV. Drug-resistance related mutations (DRMs) T369V/I and A371V in the connection subdomain (CN) of reverse transcriptase (RT) occur at higher frequencies in the individuals experiencing antiretroviral therapy failure. Here, we evaluated the effects of T369V/I and A371V on viral fitness, in the presence or in the absence of thymidine analogue resistance-associated mutations (TAMs) and assessed the effect of potential RT structure-related mechanism on change in viral fitness...
March 6, 2017: Virus Research
https://www.readbyqxmd.com/read/28276283/novel-fused-pyrimidine-and-isoquinoline-derivatives-as-potent-hiv-1-nnrtis-a-patent-evaluation-of-wo2016105532a1-wo2016105534a1-and-wo2016105564a1
#8
REVIEW
Dongwei Kang, Zhipeng Huo, Gaochan Wu, Jiabao Xu, Peng Zhan, Xinyong Liu
In the three patent applications, the impact of changing the pyrimidine core of the rilpivirine (RPV) to a variety of alternative fused cores was explored, culminating in the identification of a series of conformationally restricted compounds with comparable potencies against WT and mutant HIV-1 strains with those of efavirenz (EFV) and RPV, and higher security in the Human Ether-a-go-go-Related Gene (hERG) assay. Areas covered: The present review provides a fused pyrimidine and isoquinoline derivatives as potent HIV-1 NNRTIs, and highlights the conformational restriction strategies in the development of NNRTIs...
April 2017: Expert Opinion on Therapeutic Patents
https://www.readbyqxmd.com/read/28275195/the-product-of-the-herpes-simplex-virus-type-2-ul16-gene-is-critical-for-the-egress-of-capsids-from-the-nuclei-of-infected-cells
#9
Jie Gao, Thomas J M Hay, Bruce W Banfield
The herpes simplex virus (HSV) UL16 gene is conserved throughout the Herpesviridae and encodes a poorly understood tegument protein. The HSV-1 UL16 protein forms complexes with several viral proteins including UL11, gE, VP22 and UL21. We previously demonstrated that HSV-2 UL21 was essential for virus propagation due to the failure of DNA-containing capsids to exit the nucleus. We hypothesized that if a UL16/UL21 complex were required for nuclear egress then HSV-2 lacking UL16 would have a similar phenotype as HSV-2 lacking UL21...
March 8, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28275193/structure-based-design-of-a-soluble-prefusion-closed-hiv-1-env-trimer-with-reduced-cd4-affinity-and-improved-immunogenicity
#10
Gwo-Yu Chuang, Hui Geng, Marie Pancera, Kai Xu, Cheng Cheng, Priyamvada Acharya, Michael Chambers, Aliaksandr Druz, Yaroslav Tsybovsky, Timothy G Wanninger, Yongping Yang, Nicole A Doria-Rose, Ivelin S Georgiev, Jason Gorman, M Gordon Joyce, Sijy O'Dell, Tongqing Zhou, Adrian B McDermott, John R Mascola, Peter D Kwong
The HIV-1-envelope (Env) trimer is a target for vaccine design as well as a conformational machine that facilitates virus entry by transitioning between prefusion-closed, CD4-bound, and co-receptor-bound conformations before rearranging into a postfusion state. Vaccine designers have sought to restrict the conformation of the HIV-1-Env trimer to its prefusion-closed state, as this state is recognized by most broadly neutralizing -but not by non-neutralizing- antibodies. We previously identified a disulfide bond, I201C-A433C (DS), which stabilizes Env in the vaccine-desired prefusion-closed state...
March 8, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28275190/identification-of-serinc5-001-as-the-predominant-spliced-isoform-for-hiv-1-restriction
#11
Xianfeng Zhang, Tao Zhou, Jie Yang, Yumei Lin, Jing Shi, Xihe Zhang, Dylan A Frabutt, Xiangwei Zeng, Sunan Li, Patrick J Venta, Yong-Hui Zheng
Among the five serine incorporator (SERINC) family members, SERINC5 (Ser5) was reported to strongly inhibit HIV-1 replication, which is counteracted by Nef. Ser5 produces 5 alternatively spliced isoforms: Ser5-001 has 10 putative transmembrane domains, whereas Ser5-004, -005, -008a, and -008b do not have the last one. Here, we confirmed the strong Ser5 anti-HIV-1 activity and investigated its isoforms' expression and antiviral activity. It was found that Ser5-001 transcripts were detected at least 10-fold more than the other isoforms by real-time quantitative PCR...
March 8, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28255091/a-new-general-method-for-simultaneous-fitting-of-temperature-and-concentration-dependence-of-reaction-rates-yields-kinetic-and-thermodynamic-parameters-for-hiv-reverse-transcriptase-specificity
#12
An Li, Jessica L Ziehr, Kenneth A Johnson
Recent studies have demonstrated the dominant role of induced-fit in enzyme specificity of HIV reverse transcriptase and many other enzymes. However, relevant thermodynamic parameters are lacking and equilibrium thermodynamic methods are of no avail because the key parameters can only determined by kinetic measurement. By modifying KinTek Explorer software, we present a new general method for globally fitting data collected over a range of substrate concentrations and temperatures and apply it to HIV reverse transcriptase...
March 2, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28254696/discovery-of-uracil-bearing-dapys-derivatives-as-novel-hiv-1-nnrtis-via-crystallographic-overlay-based-molecular-hybridization
#13
Heng Zhang, Ye Tian, Dongwei Kang, Zhipeng Huo, Zhongxia Zhou, Huiqing Liu, Erik De Clercq, Christophe Pannecouque, Peng Zhan, Xinyong Liu
A novel series of uracil-bearing DAPYs derivatives were designed and synthesized via structure-based molecular hybridization to discover compounds with improved anti-resistance profiles. Anti-HIV activity of the designed compounds was tested in MT-4 cell cultures. The most promising compound 16d showed excellent activity with EC50 value of 5.6 nM against wide-type HIV-1 and low cytotoxicity (SI > 50000). Activity against the clinic prevalent mutant strains was also tested, suggesting that 16d was sensitive to E138K (EC50 = 34...
April 21, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28229507/a-samhd1-mutation-associated-with-aicardi-gouti%C3%A3-res-syndrome-uncouples-the-ability-of-samhd1-to-restrict-hiv-1-from-its-ability-to-downmodulate-type-i-interferon-in-humans
#14
Tommy E White, Alberto Brandariz-Nuñez, Alicia Martinez-Lopez, Caitlin Knowlton, Gina Lenzi, Baek Kim, Dmitri Ivanov, Felipe Diaz-Griffero
Mutations in the human SAMHD1 gene are known to correlate with the development of the Aicardi-Goutières Syndrome (AGS), which is an inflammatory encephalopathy that exhibits neurological dysfunction characterized by increased production of type I interferon (IFN); this evidence has lead to the concept that the SAMHD1 protein negatively regulates the type I IFN response. Additionally, the SAMHD1 protein has been shown to prevent efficient HIV-1 infection of macrophages, dendritic cells and resting CD4+ T cells...
February 22, 2017: Human Mutation
https://www.readbyqxmd.com/read/28218747/mhc-i-peptides-get-out-of-the-groove-and-enable-a-novel-mechanism-of-hiv-1-escape
#15
Phillip Pymm, Patricia T Illing, Sri H Ramarathinam, Geraldine M O'Connor, Victoria A Hughes, Corinne Hitchen, David A Price, Bosco K Ho, Daniel W McVicar, Andrew G Brooks, Anthony W Purcell, Jamie Rossjohn, Julian P Vivian
Major histocompatibility complex class I (MHC-I) molecules play a crucial role in immunity by capturing peptides for presentation to T cells and natural killer (NK) cells. The peptide termini are tethered within the MHC-I antigen-binding groove, but it is unknown whether other presentation modes occur. Here we show that 20% of the HLA-B*57:01 peptide repertoire comprises N-terminally extended sets characterized by a common motif at position 1 (P1) to P2. Structures of HLA-B*57:01 presenting N-terminally extended peptides, including the immunodominant HIV-1 Gag epitope TW10 (TSTLQEQIGW), showed that the N terminus protrudes from the peptide-binding groove...
February 20, 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/28202766/inhibition-of-hiv-1-maturation-via-small-molecule-targeting-of-the-amino-terminal-domain-in-the-viral-capsid-protein
#16
Weifeng Wang, Jing Zhou, Upul D Halambage, Kellie A Jurado, Augusta V Jamin, Yujie Wang, Alan N Engelman, Christopher Aiken
The HIV-1 capsid protein is an attractive therapeutic target owing to its multifunctionality in virus replication and the high fitness cost of amino acid substitutions in capsid to HIV-1 infectivity. To date, small molecule inhibitors have been identified that inhibit HIV-1 capsid assembly and/or impair its function in target cells. Here we describe the mechanism of action of the previously reported capsid-targeting HIV-1 inhibitor, BI compound 1 (C1). We show that C1 acts during HIV-1 maturation to prevent assembly of a mature viral capsid...
February 15, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28202754/jak-stat-signaling-pathways-and-inhibitors-affect-reversion-of-envelope-mutated-hiv-1
#17
Yudong Quan, Hongtao Xu, Yingshan Han, Thibault Mesplède, Mark A Wainberg
HIV can spread by both cell-free and cell-to-cell transmission. Here, we show that numerous of the amino acid changes in Env that are close to the CD4 binding pocket can affect HIV replication. We generated a number of mutant viruses that were unable to infect T cells as cell-free viruses but were nevertheless able to infect certain T cell lines as cell-associated viruses, followed by reversion to wild type. However, the activation of JAK-STAT signaling pathways caused inhibition of such cell-to-cell infection as well as the reversion of multiple HIV Env mutants that displayed differences in ability to bind to the CD4 receptor...
February 15, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28195728/room-temperature-neutron-crystallography-of-drug-resistant-hiv-1-protease-uncovers-limitations-of-x-ray-structural-analysis-at-100-k
#18
Oksana Gerlits, David A Keen, Matthew P Blakeley, John M Louis, Irene T Weber, Andrey Kovalevsky
HIV-1 protease inhibitors are crucial for treatment of HIV-1/AIDS, but their effectiveness is thwarted by rapid emergence of drug resistance. To better understand binding of clinical inhibitors to resistant HIV-1 protease, we used room-temperature joint X-ray/neutron (XN) crystallography to obtain an atomic-resolution structure of the protease triple mutant (V32I/I47V/V82I) in complex with amprenavir. The XN structure reveals a D(+) ion located midway between the inner Oδ1 oxygen atoms of the catalytic aspartic acid residues...
February 28, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28161890/homology-guided-mutational-analysis-reveals-the-functional-requirements-for-antinociceptive-specificity-of-collapsin-response-mediator-protein-2-derived-peptides
#19
Aubin Moutal, Wennan Li, Yue Wang, Weina Ju, Shizhen Luo, Song Cai, Liberty François-Moutal, Samantha Perez-Miller, Jackie Hu, Erik T Dustrude, Todd W Vanderah, Vijay Gokhale, May Khanna, Rajesh Khanna
BACKGROUND AND PURPOSE: N-type voltage-gated calcium (Cav 2.2) channels are critical determinants of increased neuronal excitability and neurotransmission accompanying persistent neuropathic pain. Although Cav 2.2 channel antagonists are recommended as first-line treatment for neuropathic pain, calcium-current blocking gabapentinoids inadequately alleviate chronic pain symptoms and often exhibit numerous side effects. Collapsin response mediator protein 2 (CRMP2) targets Cav 2.2 channels to the sensory neuron membrane and allosterically modulates their function...
February 5, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28152383/htlv-1-tax-activates-hiv-1-transcription-in-latency-models
#20
Victor Emmanuel Viana Geddes, Diego Pandeló José, Fabio E Leal, Douglas F Nixon, Amilcar Tanuri, Renato Santana Aguiar
HIV-1 latency is a major obstacle to HIV-1 eradication. Coinfection with HTLV-1 has been associated with faster progression to AIDS. HTLV-1 encodes the transactivator Tax which can activate both HTLV-1 and HIV-1 transcription. Here, we demonstrate that Tax activates HIV transcription in latent CD4(+) T cells. Tax promotes the activation of P-TEFb, releasing CDK9 and Cyclin T1 from inactive forms, promoting transcription elongation and reactivation of latent HIV-1. Tax mutants lacking interaction with the HIV-1-LTR promoter were not able to activate P-TEFb, with no subsequent activation of latent HIV...
January 30, 2017: Virology
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