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https://www.readbyqxmd.com/read/29349445/discovery-of-novel-diarylpyrimidines-as-potent-hiv-1-nnrtis-by-investigating-the-chemical-space-of-a-less-explored-hydrophobic-channel
#1
Zhongxia Zhou, Tao Liu, Dongwei Kang, Zhipeng Huo, Gaochan Wu, Dirk Daelemans, Erik De Clercq, Christophe Pannecouque, Peng Zhan, Xinyong Liu
A new series of diarylpyrimidines (DAPYs) were designed, synthesized and evaluated as novel HIV-1 NNRTIs to further explore the chemical space surrounding the "hydrophobic channel" of the NNRTI binding pocket (NNIBP), guided by the comprehensive analysis of X-ray structural biology data of HIV-1 RT/NNRTI complexes and molecular modeling. Encouragingly, most of the synthesized DAPYs were found to be active against the HIV-1 wild-type (WT) strain with EC50 values ranging from 3 nM to 63 nM, and displayed significantly reduced cytotoxicity compared with etravirine (ETV) and rilpivirine (RPV)...
January 19, 2018: Organic & Biomolecular Chemistry
https://www.readbyqxmd.com/read/29346270/resistance-to-hiv-integrase-inhibitors-about-r263k-and-e157q-mutations
#2
REVIEW
Charlotte Charpentier, Diane Descamps
The use of integrase inhibitors (INI) is increasing in antiretroviral therapies (ART) and INI are not all equal regarding genetic barrier to resistance. The aim of this manuscript was to review main in vivo and in vitro knowledge about two particular integrase resistance-associated mutations: R263K and E157Q. The R263K mutation was the first mutation rarely found selected at time of virological failure in patients failing a first-line dolutegravir-based treatment. Further in vitro studies on R263K mutants showed a moderate increase in phenotypic resistance level and a drastic reduction in viral replicative capacity...
January 18, 2018: Viruses
https://www.readbyqxmd.com/read/29342281/phenotypic-analysis-of-hiv-1-e157q-integrase-polymorphism-and-impact-on-virological-outcome-in-patients-initiating-an-integrase-inhibitor-based-regimen
#3
Charlotte Charpentier, Isabelle Malet, Elisabeth Andre-Garnier, Alexandre Storto, Laurence Bocket, Corinne Amiel, Laurence Morand-Joubert, Camille Tumiotto, Thuy Nguyen, Anne Maillard, Audrey Rodallec, Marie Leoz, Brigitte Montes, Véronique Schneider, Jean-Christophe Plantier, Julia Dina, Coralie Pallier, Audrey Mirand, Catherine Roussel, Anne Signori-Schmuck, Stéphanie Raymond, Vincent Calvez, Constance Delaugerre, Anne-Geneviève Marcelin, Diane Descamps
Objectives: To assess the phenotypic susceptibility of the E157Q polymorphism in HIV-1 integrase (IN) and the virological outcome of patients infected with E157Q-mutated virus initiating an IN inhibitor (INI)-based regimen. Methods: This was a multicentre study assessing IN sequences from INI-naive patients among 17 French HIV clinical centres. E157Q site-directed mutants in pNL4.3 and pCRF02_AG contexts were assessed in a recombinant phenotypic assay. Results: Prevalence of the E157Q polymorphism was 2...
January 12, 2018: Journal of Antimicrobial Chemotherapy
https://www.readbyqxmd.com/read/29339432/deregulation-of-hdac5-by-viral-interferon-regulatory-factor-3-plays-an-essential-role-in-kaposi-s-sarcoma-associated-herpesvirus-induced-lymphangiogenesis
#4
Hye-Ra Lee, Fan Li, Un Yung Choi, Hye Ryun Yu, Grace M Aldrovandi, Pinghui Feng, Shou-Jiang Gao, Young-Kwon Hong, Jae U Jung
Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiologic agent for Kaposi's sarcoma (KS), which is one of the most common HIV-associated neoplasms. The endothelium is the thin layer of squamous cells where vascular blood endothelial cells (BECs) line the interior surface of blood vessels and lymphatic endothelial cells (LECs) are in direct contact with lymphatic vessels. The KS lesions contain a prominent compartment of neoplastic spindle morphology cells that are closely related to LECs. Furthermore, while KSHV can infect both LECs and BECs in vitro, its infection activates genetic programming related to lymphatic endothelial cell fate, suggesting that lymphangiogenic pathways are involved in KSHV infection and malignancy...
January 16, 2018: MBio
https://www.readbyqxmd.com/read/29338752/structural-alteration-of-dna-induced-by-viral-protein-r-of-hiv-1-triggers-the-dna-damage-response
#5
Kenta Iijima, Junya Kobayashi, Yukihito Ishizaka
BACKGROUND: Viral protein R (Vpr) is an accessory protein of HIV-1, which is potentially involved in the infection of macrophages and the induction of the ataxia-telangiectasia and Rad3-related protein (ATR)-mediated DNA damage response (DDR). It was recently proposed that the SLX4 complex of structure-specific endonuclease is involved in Vpr-induced DDR, which implies that aberrant DNA structures are responsible for this phenomenon. However, the mechanism by which Vpr alters the DNA structures remains unclear...
January 16, 2018: Retrovirology
https://www.readbyqxmd.com/read/29338738/rapid-hiv-disease-progression-following-superinfection-in-an-hla-b-27-05-b-57-01-positive-transmission-recipient
#6
Jacqui Brener, Astrid Gall, Jacob Hurst, Rebecca Batorsky, Nora Lavandier, Fabian Chen, Anne Edwards, Chrissy Bolton, Reena Dsouza, Todd Allen, Oliver G Pybus, Paul Kellam, Philippa C Matthews, Philip J R Goulder
BACKGROUND: The factors determining differential HIV disease outcome among individuals expressing protective HLA alleles such as HLA-B*27:05 and HLA-B*57:01 remain unknown. We here analyse two HIV-infected subjects expressing both HLA-B*27:05 and HLA-B*57:01. One subject maintained low-to-undetectable viral loads for more than a decade of follow up. The other progressed to AIDS in < 3 years. RESULTS: The rapid progressor was the recipient within a known transmission pair, enabling virus sequences to be tracked from transmission...
January 16, 2018: Retrovirology
https://www.readbyqxmd.com/read/29330371/transcriptional-inaccuracy-threshold-attenuates-differences-in-rna-dependent-dna-synthesis-fidelity-between-retroviral-reverse-transcriptases
#7
Alba Sebastián-Martín, Verónica Barrioluengo, Luis Menéndez-Arias
In M13mp2 lacZα forward mutation assays measuring intrinsic fidelity of DNA-dependent DNA synthesis, wild-type human immunodeficiency virus type 1 (HIV-1) RTs of group M/subtype B previously showed >10-fold higher error rates than murine leukaemia virus (MLV) and avian myeloblastosis virus (AMV) RTs. An adapted version of the assay was used to obtain error rates of RNA-dependent DNA synthesis for several RTs, including wild-type HIV-1BH10, HIV-1ESP49, AMV and MLV RTs, and the high-fidelity mutants of HIV-1ESP49 RT K65R and K65R/V75I...
January 12, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29321964/introduction-of-h2c2-type-zinc-binding-residues-into-hiv-2-vpr-increases-its-expression-level
#8
Ryoko Koga, Minami Yamamoto, Halil Ibrahim Ciftci, Masami Otsuka, Mikako Fujita
Human immunodeficiency virus type 2 has two structurally similar proteins, Vpx and Vpr. Vpx degrades the host anti-viral protein SAMHD1 and is expressed at high levels, while Vpr is responsible for cell cycle arrest and is expressed at much lower levels. We constructed a Vpr mutant with a high level of expression by replacing the amino acids HHCR/HHCH with a putative H2C2-type zinc-binding site that is carried by Vpx. Our finding suggests that during the evolution of Vpr and Vpx, zinc-binding likely became a mechanism for regulating their expression levels...
January 2018: FEBS Open Bio
https://www.readbyqxmd.com/read/29321334/mechanism-of-hiv-1-resistance-to-an-electronically-constrained-%C3%AE-helical-peptide-membrane-fusion-inhibitor
#9
Xiyuan Wu, Zixuan Liu, Xiaohui Ding, Danwei Yu, Huamian Wei, Bo Qin, Yuanmei Zhu, Huihui Chong, Sheng Cui, Yuxian He
SC29EK is an electronically constrained α-helical peptide HIV-1 fusion inhibitor highly effective against both wild-type and enfuvirtide (T20)-resistant viruses. In this study, we focused on investigating the mechanism of HIV-1 resistance to SC29EK by two approaches. First, SC29EK-escaping HIV-1 variants were selected and characterized. Three mutant viruses, which possessed two (E43K/E49A) or three (Q39R/N43K/N126K, N43K/E49A/N126K) amino acid substitutions in the N- and C-terminal repeat regions of gp41 were identified as conferring high resistance to SC29EK and cross-resistance to the first-generation (T20, C34) and newly-designed (sifuvirtide, MT-SC29EK, 2P23) fusion inhibitors...
January 10, 2018: Journal of Virology
https://www.readbyqxmd.com/read/29321329/a-cyclin-binding-motif-in-human-samhd1-is-required-for-its-hiv-1-restriction-dntpase-activity-tetramer-formation-and-efficient-phosphorylation
#10
Corine St Gelais, Sun Hee Kim, Victoria V Maksimova, Olga Buzovetsky, Kirsten Knecht, Caitlin Shepard, Baek Kim, Yong Xiong, Li Wu
Sterile alpha motif and HD domain-containing protein 1 (SAMHD1) regulates intracellular deoxynucleoside triphosphate (dNTP) levels and functions as a retroviral restriction factor through its dNTP triphosphohydrolase (dNTPase) activity. Human SAMHD1 interacts with cell cycle regulatory proteins cyclin A2, cyclin-dependent kinase 1 (CDK1), and CDK2. This interaction mediates phosphorylation of SAMHD1 at threonine 592 (T592), which negatively regulates HIV-1 restriction. We previously reported that the interaction is mediated, at least in part, through a cyclin-binding motif (RXL, aa...
January 10, 2018: Journal of Virology
https://www.readbyqxmd.com/read/29303997/high-mannose-but-not-complex-type-glycosylation-of-tetherin-is-required-for-restriction-of-hiv-1-release
#11
Abdul A Waheed, Ariana Gitzen, Maya Swiderski, Eric O Freed
Tetherin is an interferon-inducible antiviral protein that inhibits the release of a broad spectrum of enveloped viruses by retaining virions at the surface of infected cells. While the role of specific tetherin domains in antiviral activity is clearly established, the role of glycosylation in tetherin function is not clear. In this study, we carried out a detailed investigation of this question by using tetherin variants in which one or both sites of N-linked glycosylation were mutated (N65A, N92A, and N65,92A), and chemical inhibitors that prevent glycosylation at specific stages of oligosaccharide were added or modified...
January 5, 2018: Viruses
https://www.readbyqxmd.com/read/29290613/the-antiviral-and-cancer-genomic-dna-deaminase-apobec3h-is-regulated-by-an-rna-mediated-dimerization-mechanism
#12
Nadine M Shaban, Ke Shi, Kate V Lauer, Michael A Carpenter, Christopher M Richards, Daniel Salamango, Jiayi Wang, Michael W Lopresti, Surajit Banerjee, Rena Levin-Klein, William L Brown, Hideki Aihara, Reuben S Harris
Human APOBEC3H and homologous single-stranded DNA cytosine deaminases are unique to mammals. These DNA-editing enzymes function in innate immunity by restricting the replication of viruses and transposons. APOBEC3H also contributes to cancer mutagenesis. Here, we address the fundamental nature of RNA in regulating human APOBEC3H activities. APOBEC3H co-purifies with RNA as an inactive protein, and RNase A treatment enables strong DNA deaminase activity. RNA-binding-defective mutants demonstrate clear separation of function by becoming DNA hypermutators...
January 4, 2018: Molecular Cell
https://www.readbyqxmd.com/read/29280955/immune-modulation-of-nyvac-based-hiv-vaccines-by-combined-deletion-of-viral-genes-that-act-on-several-signalling-pathways
#13
Carmen Elena Gómez, Beatriz Perdiguero, Cristina Sánchez-Corzo, Carlos Oscar S Sorzano, Mariano Esteban
An HIV-1 vaccine continues to be a major target to halt the AIDS pandemic. The limited efficacy of the RV144 phase III clinical trial with the canarypox virus-based vector ALVAC and a gp120 protein component led to the conclusion that improved immune responses to HIV antigens are needed for a more effective vaccine. In non-human primates, the New York vaccinia virus (NYVAC) poxvirus vector has a broader immunogenicity profile than ALVAC and has been tested in clinical trials. We therefore analysed the HIV immune advantage of NYVAC after removing viral genes that act on several signalling pathways (Toll-like receptors-TLR-interferon, cytokines/chemokines), as well as genes of unknown immune function...
December 27, 2017: Viruses
https://www.readbyqxmd.com/read/29275329/amino-acid-residues-in-hiv-2-reverse-transcriptase-that-restrict-the-development-of-nucleoside-analogue-resistance-through-the-excision-pathway
#14
Mar Álvarez, Maria Nevot, Jesus Mendieta, Miguel A Martinez, Luis Menéndez-Arias
Nucleoside reverse transcriptase (RT) inhibitors (NRTIs) are the backbone of current antiretroviral treatments. However, emergence of viral resistance against NRTIs is a major threat to their therapeutic effectiveness. In HIV-1, NRTI resistance-associated mutations either reduce RT-mediated incorporation of NRTI triphosphates (discrimination mechanism) or confer an ATPmediated nucleotide excision activity that removes the inhibitor from the 3'-terminus of DNA primers, enabling further primer elongation (excision mechanism)...
December 22, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29258818/remodeling-of-hiv-1-nef-structure-by-src-family-kinase-binding
#15
Jamie A Moroco, John Jeff Alvarado, Ryan P Staudt, Haibin Shic, Thomas E Wales, Thomas E Smithgall, John R Engen
The HIV-1 accessory protein Nef controls multiple aspects of the viral life cycle and host immune response, making it an attractive therapeutic target. Previous X-ray crystal structures of Nef in complex with key host cell binding partners have shed light on protein-protein interactions critical to Nef function. Crystal structures of Nef in complex with either the SH3 or tandem SH3-SH2 domains of Src-family kinases reveal distinct dimer conformations of Nef. However, the existence of these Nef dimer complexes in solution has not been established...
December 16, 2017: Journal of Molecular Biology
https://www.readbyqxmd.com/read/29258557/moloney-leukemia-virus-10-mov10-inhibits-the-degradation-of-apobec3g-through-interference-with-the-vif-mediated-ubiquitin-proteasome-pathway
#16
Cancan Chen, Xiaocao Ma, Qifei Hu, Xinghua Li, Feng Huang, Junsong Zhang, Ting Pan, Jinyu Xia, Chao Liu, Hui Zhang
BACKGROUND: MOV10 protein has ATP-dependent 5'-3' RNA helicase activity and belongs to the UPF1p superfamily. It can inhibit human immunodeficiency virus type 1 (HIV-1) replication at multiple stages and interact with apolipoprotein-B-mRNA-editing enzyme catalytic polypeptide-like 3G (APOBEC3G or A3G), a member of the cytidine deaminase family that exerts potent inhibitory effects against HIV-1 infection. However, HIV-1-encoded virion infectivity factor (Vif) protein specifically mediates the degradation of A3G via the ubiquitin-proteasome system (UPS)...
December 19, 2017: Retrovirology
https://www.readbyqxmd.com/read/29239895/development-of-broad-neutralization-activity-in-shiv-infected-rhesus-macaques-after-long-term-infection
#17
Nan Gao, Wei Wang, Chu Wang, Tiejun Gu, Rui Guo, Bin Yu, Wei Kong, Chuan Qin, Elena E Giorgi, Zhiwei Chen, Samantha Townsley, Shiu-Lok Hu, Xianghui Yu, Feng Gao
OBJECTIVE: Non-human primates (NHPs) are the only animal model that can be used to evaluate protection efficacy of HIV-1 Env vaccines. However, whether broadly neutralizing antibodies (bnAbs) can be elicited in NHPs infected with simian/human immunodeficiency virus (SHIV) has not been fully understood. The objective of this study is to investigate whether broad neutralization activities were developed in SHIV-infected macaques after long-term infection as in humans. DESIGN: Neutralization breadth and specificities in plasmas from SHIV-infected macaques could be determined by analyzing a panel of tier 2 viruses and their mutants...
December 12, 2017: AIDS
https://www.readbyqxmd.com/read/29229373/paper-based-detection-of-hiv-1-drug-resistance-using-isothermal-amplification-and-an-oligonucleotide-ligation-assay
#18
Mary E Natoli, Brittany A Rohrman, Carolina de Santiago, Gert U van Zyl, Rebecca R Richards-Kortum
Regular HIV-1 viral load monitoring is the standard of care to assess antiretroviral therapy effectiveness in resource-rich settings. Persistently elevated viral loads indicate virologic failure (VF), which warrants HIV drug resistance testing (HIVDRT) to allow individualized regimen switches. However, in settings lacking access to HIVDRT, clinical decisions are often made based on symptoms, leading to unnecessary therapy switches and increased costs of care. This work presents a proof-of-concept assay to detect M184V, the most common drug resistance mutation after first-line antiretroviral therapy failure, in a paper format...
December 8, 2017: Analytical Biochemistry
https://www.readbyqxmd.com/read/29228272/an-investigation-into-the-possible-regulation-of-the-expression-of-genes-by-yapa-in-talaromyces-marneffei-using-the-qrt-pcr-method
#19
Wiyada Dankai, Monsicha Pongpom, Nongnuch Vanittanakom
The pathogenic dimorphic fungus Talaromyces marneffei is known to cause a fatal systemic mycosis in immunocompromised patients, especially in HIV patients in Southeast Asia. The basic leucine-zipper (bZip) transcription factor gene, yapA, has been identified in T. marneffei. A prior study described that yapA was involved in the oxidative and nitrosative stress response in T. marneffei. Interestingly, an essential role of Saccharomyces cerevisiae Yap1p in the oxidative stress response is the activation of the transcription of its target genes...
December 8, 2017: Medical Mycology: Official Publication of the International Society for Human and Animal Mycology
https://www.readbyqxmd.com/read/29212937/experimental-adaptive-evolution-of-sivcpz-to-pandemic-hiv-1-using-a-humanized-mouse-model
#20
Kei Sato, Naoko Misawa, Junko S Takeuchi, Tomoko Kobayashi, Taisuke Izumi, Hirofumi Aso, Shumpei Nagaoka, Keisuke Yamamoto, Izumi Kimura, Yoriyuki Konno, Yusuke Nakano, Yoshio Koyanagi
HIV-1, the causative agent of AIDS, is originated from SIVcpz, the chimpanzee precursor of the human virus, approximately 100 years ago. This indicates that HIV-1 has emerged through the cross-species transmission of SIVcpz from chimpanzees to humans. However, it remains unclear how SIVcpz has evolved into pandemic HIV-1 in humans. To address this question, we inoculated three SIVcpz (MB897, EK505, and MT145), four pandemic HIV-1 (NL4-3, NLCSFV3, JRCSF and AD8) and 2 non-pandemic HIV-1 (YBF30 and DJO0131) strains...
December 6, 2017: Journal of Virology
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