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https://www.readbyqxmd.com/read/28056217/zinc-binding-site-of-hiv-2-vpx-prevents-instability-and-dysfunction-of-the-protein
#1
Minami Yamamoto, Ryoko Koga, Haruna Fujino, Kazunori Shimagaki, Halil Ibrahim Ciftci, Masahiro Kamo, Hiroshi Tateishi, Masami Otsuka, Mikako Fujita
HIV-2 Vpx coordinates zinc through residues H39, H82, C87 and C89. We reported previously that H39, H82 and C87 mutants maintain Vpx activity to facilitate the degradation of SAMHD1. Herein, the expression of Vpx mutants in cells was examined in detail. We demonstrated that the zinc-binding site stabilizes the protein to keep its function in virus growth when low levels of Vpx are expressed. At higher levels of expression, Vpx aggregation can occur, and zinc binding would suppress such aggregation. Among the amino acids involved in zinc coordination, H39 plays the most critical role...
January 5, 2017: Journal of General Virology
https://www.readbyqxmd.com/read/28032867/regulation-of-er-stress-induced-autophagy-by-gsk3%C3%AE-tip60-ulk1-pathway
#2
Tiejian Nie, Shaosong Yang, Hongwei Ma, Lei Zhang, Fangfang Lu, Kai Tao, Ronglin Wang, Ruixin Yang, Lu Huang, Zixu Mao, Qian Yang
Endoplasmic reticulum (ER) stress is involved in many cellular processes. Emerging evidence suggests that ER stress can trigger autophagy; however, the mechanisms by which ER stress regulates autophagy and its role in this condition are not fully understood. HIV Tat-interactive protein, 60 kDa (TIP60) is a newly discovered acetyltransferase that can modulate autophagy flux by activating ULK1 upon growth factor deprivation. In this study, we investigated the mechanisms by which ER stress induces autophagy...
December 29, 2016: Cell Death & Disease
https://www.readbyqxmd.com/read/28031466/cell-based-fluorescence-complementation-reveals-a-role-for-hiv-1-nef-dimerization-in-ap-2-recruitment-and-cd4-downregulation
#3
Sherry T Shu, Lori A Emert-Sedlak, Thomas E Smithgall
The HIV-1 Nef accessory factor enhances viral infectivity, immune evasion, and AIDS progression. Nef triggers rapid downregulation of CD4 via the endocytic adaptor protein 2 (AP-2) complex, a process linked to enhanced viral infectivity and immune escape. Here we describe a bimolecular fluorescence complementation (BiFC) assay to visualize the interaction of Nef with AP-2 and CD4 in living cells. Interacting protein pairs were fused to complementary, non-fluorescent fragments of YFP and co-expressed in 293T cells...
December 28, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28031368/the-structural-interface-between-hiv-1-vif-and-human-apobec3h
#4
Marcel Ooms, Michael Letko, Viviana Simon
: Human APOBEC3H (A3H) is a cytidine deaminase that inhibits HIV-1 replication. To evade this restriction, the HIV-1 Vif protein binds A3H and mediates its proteasomal degradation. To date, little information on the Vif-A3H interface is available. To decipher how both proteins interact we first mapped the Vif-binding site on A3H by functionally testing a large set of A3H mutants in single cycle infectivity and replication assays. Our data show that the two A3H α-helixes α3 and α4 represent the Vif-binding site of A3H...
December 28, 2016: Journal of Virology
https://www.readbyqxmd.com/read/28002960/characterization-of-new-cationic-n-n-dimethyl-70-fulleropyrrolidinium-iodide-derivatives-as-potent-hiv-1-maturation-inhibitors
#5
Edison Castro, Zachary S Martinez, Chang-Soo Seong, Andrea Cabrera-Espinoza, Mauro Ruiz, Andrea Hernandez Garcia, Federico Valdez, Manuel Llano, Luis Echegoyen
HIV-1 maturation can be impaired by altering protease (PR) activity, the structure of the Gag-Pol substrate, or the molecular interactions of viral structural proteins. Here we report the synthesis and characterization of new cationic N,N-dimethyl[70]fulleropyrrolidinium iodide derivatives that inhibit more than 99% of HIV-1 infectivity at low micromolar concentrations. Analysis of the HIV-1 life cycle indicated that these compounds inhibit viral maturation by impairing Gag and Gag-Pol processing. Importantly, fullerene derivatives 2a-c did not inhibit in vitro PR activity and strongly interacted with HIV immature capsid protein in pull-down experiments...
December 22, 2016: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27999055/unravelling-the-dynamics-of-selection-of-multiresistant-variants-to-integrase-inhibitors-in-an-hiv-1-infected-child-using-ultra-deep-sequencing
#6
Karl Stefic, Maud Salmona, Marisa Capitao, Marion Splittgerber, Zoha Maakaroun-Vermesse, Marie-Laure Néré, Louis Bernard, Marie-Laure Chaix, Francis Barin, Constance Delaugerre
BACKGROUND: Ultra-deep sequencing (UDS) allows detection of minority resistant variants (MRVs) with a threshold of 1% and could be useful to identify variants harbouring single or multiple drug-resistance mutations (DRMs). OBJECTIVES: We analysed the integrase gene region longitudinally using UDS in an HIV-1-infected child rapidly failing a raltegravir-based regimen. METHODS: Longitudinal plasma samples at baseline and weeks 4, 8, 13, 17 and 39 were obtained, as well as the mother's baseline plasma sample...
December 20, 2016: Journal of Antimicrobial Chemotherapy
https://www.readbyqxmd.com/read/27998286/ultrasensitive-single-genome-sequencing-accurate-targeted-next-generation-sequencing-of-hiv-1-rna
#7
Valerie F Boltz, Jason Rausch, Wei Shao, Junko Hattori, Brian Luke, Frank Maldarelli, John W Mellors, Mary F Kearney, John M Coffin
BACKGROUND: Although next generation sequencing (NGS) offers the potential for studying virus populations in unprecedented depth, PCR error, amplification bias and recombination during library construction have limited its use to population sequencing and measurements of unlinked allele frequencies. Here we report a method, termed ultrasensitive Single-Genome Sequencing (uSGS), for NGS library construction and analysis that eliminates PCR errors and recombinants, and generates single-genome sequences of the same quality as the "gold-standard" of HIV-1 single-genome sequencing assay but with more than 100-fold greater depth...
December 20, 2016: Retrovirology
https://www.readbyqxmd.com/read/27992602/receptor-activation-of-hiv-1-env-leads-to-asymmetric-exposure-of-the-gp41-trimer
#8
Mukta D Khasnis, Konstantine Halkidis, Anshul Bhardwaj, Michael J Root
Structural rearrangements of HIV-1 glycoprotein Env promote viral entry through membrane fusion. Env is a symmetric homotrimer with each protomer composed of surface subunit gp120 and transmembrane subunit gp41. Cellular CD4- and chemokine receptor-binding to gp120 coordinate conformational changes in gp41, first to an extended prehairpin intermediate (PHI) and, ultimately, into a fusogenic trimer-of-hairpins (TOH). HIV-1 fusion inhibitors target gp41 in the PHI and block TOH formation. To characterize structural transformations into and through the PHI, we employed asymmetric Env trimers containing both high and low affinity binding sites for individual fusion inhibitors...
December 2016: PLoS Pathogens
https://www.readbyqxmd.com/read/27992544/structural-studies-of-a-rationally-selected-multi-drug-resistant-hiv-1-protease-reveal-synergistic-effect-of-distal-mutations-on-flap-dynamics
#9
Johnson Agniswamy, John M Louis, Julien Roche, Robert W Harrison, Irene T Weber
We report structural analysis of HIV protease variant PRS17 which was rationally selected by machine learning to represent wide classes of highly drug-resistant variants. Crystal structures were solved of PRS17 in the inhibitor-free form and in complex with antiviral inhibitor, darunavir. Despite its 17 mutations, PRS17 has only one mutation (V82S) in the inhibitor/substrate binding cavity, yet exhibits high resistance to all clinical inhibitors. PRS17 has none of the major mutations (I47V, I50V, I54ML, L76V and I84V) associated with darunavir resistance, but has 10,000-fold weaker binding affinity relative to the wild type PR...
2016: PloS One
https://www.readbyqxmd.com/read/27992346/prediction-of-hiv-drug-resistance-by-combining-sequence-and-structural-properties
#10
Zoya Khalid, Osman Ugur Sezerman
Drug resistance is a major obstacle faced by therapist in treating HIV infected patients. The reason behind these phenomena is either protein mutation or the changes in gene expression level that induces resistance to drug treatments. These mutations affect the drug binding activity, hence resulting in failure of treatment. Therefore, it is necessary to conduct resistance testing in order to carry out HIV effective therapy. This study combines both sequence and structural features for predicting HIV resistance by applying SVM and Random Forests classifiers...
December 13, 2016: IEEE/ACM Transactions on Computational Biology and Bioinformatics
https://www.readbyqxmd.com/read/27966610/molecular-mechanism-the-human-dopamine-transporter-histidine-547-regulates-basal-and-hiv-1-tat-protein-inhibited-dopamine-transport
#11
Pamela M Quizon, Wei-Lun Sun, Yaxia Yuan, Narasimha M Midde, Chang-Guo Zhan, Jun Zhu
Abnormal dopaminergic transmission has been implicated as a risk determinant of HIV-1-associated neurocognitive disorders. HIV-1 Tat protein increases synaptic dopamine (DA) levels by directly inhibiting DA transporter (DAT) activity, ultimately leading to dopaminergic neuron damage. Through integrated computational modeling prediction and experimental validation, we identified that histidine547 on human DAT (hDAT) is critical for regulation of basal DA uptake and Tat-induced inhibition of DA transport. Compared to wild type hDAT (WT hDAT), mutation of histidine547 (H547A) displayed a 196% increase in DA uptake...
December 14, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27959928/an-efficient-microarray-based-genotyping-platform-for-the-identification-of-drug-resistance-mutations-in-majority-and-minority-subpopulations-of-hiv-1-quasispecies
#12
Verónica Martín, Celia Perales, María Fernández-Algar, Helena G Dos Santos, Patricia Garrido, María Pernas, Víctor Parro, Miguel Moreno, Javier García-Pérez, José Alcamí, José Luis Torán, David Abia, Esteban Domingo, Carlos Briones
The response of human immunodeficiency virus type 1 (HIV-1) quasispecies to antiretroviral therapy is influenced by the ensemble of mutants that composes the evolving population. Low-abundance subpopulations within HIV-1 quasispecies may determine the viral response to the administered drug combinations. However, routine sequencing assays available to clinical laboratories do not recognize HIV-1 minority variants representing less than 25% of the population. Although several alternative and more sensitive genotyping techniques have been developed, including next-generation sequencing (NGS) methods, they are usually very time consuming, expensive and require highly trained personnel, thus becoming unrealistic approaches in daily clinical practice...
2016: PloS One
https://www.readbyqxmd.com/read/27936595/physiological-mg-2-conditions-significantly-alter-the-inhibition-of-hiv-1-and-hiv-2-reverse-transcriptases-by-nucleoside-and-non-nucleoside-inhibitors-in-vitro
#13
Vasudevan Achuthan, Kamlendra Singh, Jeffrey J DeStefano
Reverse transcriptases (RTs) are typically assayed in vitro with 5-10 mM Mg(2+), whereas the free Mg(2+) concentration in cells is much lower. Artificially high Mg(2+) concentrations used in vitro can misrepresent different properties of human immunodeficiency virus (HIV) RT, including fidelity, catalysis, pausing, and RNase H activity. Here, we analyzed nucleoside (NRTIs) and non-nucleoside RT inhibitors (NNRTIs) in primer extension assays at different concentrations of free Mg(2+). At low concentrations of Mg(2+), NRTIs and dideoxynucleotides (AZTTP, ddCTP, ddGTP, and 3TCTP) inhibited HIV-1 and HIV-2 RT synthesis less efficiently than they did with large amounts of Mg(2+), whereas inhibition by the "translocation-defective RT inhibitor" EFdA (4'-ethynyl-2-fluoro-2'-deoxyadenosine) was unaffected by Mg(2+) concentrations...
December 27, 2016: Biochemistry
https://www.readbyqxmd.com/read/27935939/structural-basis-for-inhibitor-induced-aggregation-of-hiv-integrase
#14
Kushol Gupta, Vesa Turkki, Scott Sherrill-Mix, Young Hwang, Grant Eilers, Louis Taylor, Charlene McDanal, Ping Wang, David Temelkoff, Robert T Nolte, Emile Velthuisen, Jerry Jeffrey, Gregory D Van Duyne, Frederic D Bushman
The allosteric inhibitors of integrase (termed ALLINIs) interfere with HIV replication by binding to the viral-encoded integrase (IN) protein. Surprisingly, ALLINIs interfere not with DNA integration but with viral particle assembly late during HIV replication. To investigate the ALLINI inhibitory mechanism, we crystallized full-length HIV-1 IN bound to the ALLINI GSK1264 and determined the structure of the complex at 4.4 Å resolution. The structure shows GSK1264 buried between the IN C-terminal domain (CTD) and the catalytic core domain...
December 2016: PLoS Biology
https://www.readbyqxmd.com/read/27907055/effect-of-glu12-his89-interaction-on-dynamic-structures-in-hiv-1-p17-matrix-protein-elucidated-by-nmr
#15
Yuta Konagaya, Rina Miyakawa, Masumi Sato, Akimasa Matsugami, Satoru Watanabe, Fumiaki Hayashi, Takanori Kigawa, Chiaki Nishimura
To test the existence of the salt bridge and stability of the HIV-1 p17 matrix protein, an E12A (mutated at helix 1) was established to abolish possible electrostatic interactions. The chemical shift perturbation from the comparison between wild type and E12A suggested the existence of an electrostatic interaction in wild type between E12 and H89 (located in helix 4). Unexpectedly, the studies using urea denaturation indicated that the E12A substitution slightly stabilized the protein. The dynamic structure of E12A was examined under physiological conditions by both amide proton exchange and relaxation studies...
2016: PloS One
https://www.readbyqxmd.com/read/27903797/accumulation-of-pol-mutations-selected-by-hla-b-52-01-c-12-02-protective-haplotype-restricted-ctls-causes-low-plasma-viral-load-due-to-low-viral-fitness-of-mutant-viruses
#16
Hayato Murakoshi, Madoka Koyanagi, Takayuki Chikata, Mohammad Arif Rahman, Nozomi Kuse, Keiko Sakai, Hiroyuki Gatanaga, Shinichi Oka, Masafumi Takiguchi
: HLA-B*52:01-C*12:02, which is the most abundant haplotype in Japan, has a protective effect on disease progression in HIV-1-infected Japanese individuals, whereas HLA-B*57 and -B*27 protective alleles are very rare in Japan. A previous study on HLA-associated polymorphisms demonstrated that the number of HLA-B*52:01-associated mutations at four Pol positions was inversely correlated with plasma viral load (pVL) in HLA-B*52:01-negative individuals, suggesting that the transmission of HIV-1 with these mutations could modulate the pVL in the population...
November 30, 2016: Journal of Virology
https://www.readbyqxmd.com/read/27902325/targeting-naturally-occurring-epitope-variants-of-hepatitis-c-virus-with-high-affinity-t-cell-receptors
#17
Huajun Zhang, Jianbing Zhang, Lei Chen, Zhiming Weng, Ye Tian, Haifeng Zhao, Youjia Li, Lin Chen, Zhaoduan Liang, Hongjun Zheng, Wenzhuo Zhao, Shi Zhong, Yi Li
Hepatitis C virus (HCV) readily establishes chronic infection, which is characterized by failure of virus-specific CD8+ T cells. HCV uses epitope mutation and T-cell exhaustion to escape from the host immune response. Previously, we engineered high-affinity T-cell receptors (HATs) targeting HIV escape mutants. In this study, the affinity of a T-cell receptor specific for the human leukocyte antigen (HLA)-A2-restricted HCV immunodominant epitope NS3 1406-1415 (KLVALGINAV) was improved from a KD of 6.6 µM to 40 pM...
November 11, 2016: Journal of General Virology
https://www.readbyqxmd.com/read/27900665/use-of-capillary-electrophoresis-to-study-the-binding-interaction-of-aptamers-with-wild-type-k103n-and-double-mutant-k103n-y181c-hiv-1-rt-studying-the-binding-interaction-of-wild-type-k103n-and-double-mutant-k103n-y181c-hiv-1-rt-with-aptamers-by-performing
#18
Niran Aeksiri, Chompunuch Warakulwit, Supa Hannongbua, Sasimanas Unajak, Kiattawee Choowongkomon
A number of nucleic acid aptamers with high affinities to human immunodeficiency virus reverse transcriptase (HIV-1 RT) are currently known. They can potentially be developed as broad-spectrum antiviral drugs, but there is little known about their binding interaction with mutant HIV-1 RT. Therefore, we utilized non-equilibrium capillary electrophoresis of equilibrium mixture (NECEEM) to study the interaction of three HIV-1 RTs (wild type, K103N, and double mutant (K103N/Y181C)) with RT1t49 and RT12 aptamers...
November 30, 2016: Applied Biochemistry and Biotechnology
https://www.readbyqxmd.com/read/27876849/characterization-of-two-distinct-early-post-entry-blocks-to-hiv-1-in-common-marmoset-lymphocytes
#19
Beatriz Pacheco, Luis Menéndez-Arias, Joseph Sodroski
In nature, primate lentiviruses infect humans and several Old World monkeys and apes. However, to date, lentiviruses infecting New World monkeys have not been described. We studied the susceptibility of common marmoset cells to HIV-1 infection and observed the presence of post-entry blocks to the early phase of HIV-1 infection in peripheral blood lymphocytes (PBLs) and a B lymphocytic cell line (B-LCL). The blocks present in these cells are dominant and phenotypically different from each other. In PBLs, the block occurs at the level of reverse transcription, reducing the accumulation of early and late transcripts, similar to the block imposed by TRIM5α...
November 23, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27875973/structural-modifications-of-diarylpyrimidine-quinolone-hybrids-as-potent-hiv-1-nnrtis-with-an-improved-drug-resistance-profile
#20
Tian-Qi Mao, Qiu-Qin He, Wen-Xue Chen, Gang-Feng Tang, Fen-Er Chen, Erik De Clercq, Dirk Daelemans, Christophe Pannecouque
Earlier we reported the identification of diarylpyrimidine-quinolone hybrids as a new class of HIV-1 NNRTIs. A few of these hybrids displayed moderate inhibitory activity against wt HIV-1 replication at submicromolar level, however, all of them lacked inhibitory activity against the double mutant virus (K103N/Y181C), which is the most prevalent NNRTI resistant-associated double mutant observed in the clinic. In the present study, we designed and synthesized a new series of diarylpyrimidine-quinolone hybrids featuring a halogen group at C-6' position of quinolone ring...
November 22, 2016: Current Pharmaceutical Design
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