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https://www.readbyqxmd.com/read/28220857/samhd1-enhances-nucleoside-analogue-efficacy-against-hiv-1-in-myeloid-cells
#1
Paula Ordonez, Simone Kunzelmann, Harriet C T Groom, Melvyn W Yap, Simon Weising, Chris Meier, Kate N Bishop, Ian A Taylor, Jonathan P Stoye
SAMHD1 is an intracellular enzyme that specifically degrades deoxynucleoside triphosphates into component nucleoside and inorganic triphosphate. In myeloid-derived dendritic cells and macrophages as well as resting T-cells, SAMHD1 blocks HIV-1 infection through this dNTP triphosphohydrolase activity by reducing the cellular dNTP pool to a level that cannot support productive reverse transcription. We now show that, in addition to this direct effect on virus replication, manipulating cellular SAMHD1 activity can significantly enhance or decrease the anti-HIV-1 efficacy of nucleotide analogue reverse transcription inhibitors presumably as a result of modulating dNTP pools that compete for recruitment by viral polymerases...
February 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28220254/hiv-1-persistent-viremia-is-frequently-followed-by-episodes-of-low-level-viremia
#2
Marek Widera, Miriam Dirks, Barbara Bleekmann, Robert Jablonka, Martin Däumer, Hauke Walter, Robert Ehret, Jens Verheyen, Stefan Esser
After the start of antiretroviral therapy (ART), plasma HIV-RNA levels should fall below the limit of detection (LOD) within 24 weeks. Hence, the prolonged decline of HIV-RNA after ART initiation is defined as persistent viremia (PV). In this retrospective study, we analyzed factors associated with PV. Next-generation sequencing of viral RNA/DNA was performed to study viral evolution and the emergence of drug-resistance mutations in HIV-infected patients with PV (n = 20). In addition, HIV-DNA species, immunological parameters, and clinical data of the patients were analyzed...
February 20, 2017: Medical Microbiology and Immunology
https://www.readbyqxmd.com/read/28219769/epitranscriptomic-regulation-of-viral-replication
#3
REVIEW
Camila Pereira-Montecinos, Fernando Valiente-Echeverría, Ricardo Soto-Rifo
RNA plays central roles in biology and novel functions and regulation mechanisms are constantly emerging. To accomplish some of their functions within the cell, RNA molecules undergo hundreds of chemical modifications from which N6-methyladenosine (m(6)A), inosine (I), pseudouridine (ψ) and 5-methylcytosine (5mC) have been described in eukaryotic mRNA. Interestingly, the m(6)A modification was shown to be reversible, adding novel layers of regulation of gene expression through what is now recognized as epitranscriptomics...
February 17, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28219762/evaluation-of-the-performances-of-twelve-rapid-diagnostic-tests-for-diagnosis-of-hiv-infection-in-yaounde-cameroon
#4
Richard Njouom, Laure Ngono, Desirée Denise Mekinda-Gometi, Cyprien Kengne Ndé, Serge Alain Sadeuh-Mba, Marie-Astrid Vernet, Patrice Tchendjou, Guy Vernet
According to the WHO/UNAIDS recommendations, an acceptable HIV rapid diagnostic tests (RDTs) has to perform a sensitivity ≥ 99% and a specificity ≥ 98%. Given the constant release of new RDTs for HIV testing in the market and the high HIV genetic diversity in Cameroon, it is interesting to monitor their performances in that setting. A total of 240 HIV positive (including 219 HIV-1M, 15 HIV-1 O, 1 HIV-1N, 1 HIV-1M/O recombinant and 4 HIV-2) and 240 HIV negative plasma samples were used to evaluate twelve routinely used RDTs in Cameroon...
February 17, 2017: Journal of Virological Methods
https://www.readbyqxmd.com/read/28219610/bictegravir-versus-dolutegravir-each-with-emtricitabine-and-tenofovir-alafenamide-for-initial-treatment-of-hiv-1-infection-a-randomised-double-blind-phase-2-trial
#5
Paul E Sax, Edwin DeJesus, Gordon Crofoot, Douglas Ward, Paul Benson, Robin Dretler, Anthony Mills, Cynthia Brinson, Julie Peloquin, Xuelian Wei, Kirsten White, Andrew Cheng, Hal Martin, Erin Quirk
BACKGROUND: All recent treatment guidelines recommend integrase strand transfer inhibitors (INSTIs) as components of initial HIV therapy. Bictegravir, a novel, once-daily, unboosted INSTI, showed potent activity in a 10 day monotherapy study and has a high in-vitro resistance barrier. On the basis of these results, we did a phase 2 trial comparing bictegravir with dolutegravir. METHODS: In this randomised, double-blind, phase 2 trial, we recruited previously untreated adults (aged ≥18 years) with HIV-1 infections from 22 outpatient centres in the USA...
February 14, 2017: Lancet HIV
https://www.readbyqxmd.com/read/28218750/quaternary-contact-in-the-initial-interaction-of-cd4-with-the-hiv-1-envelope-trimer
#6
Qingbo Liu, Priyamvada Acharya, Michael A Dolan, Peng Zhang, Christina Guzzo, Jacky Lu, Alice Kwon, Deepali Gururani, Huiyi Miao, Tatsiana Bylund, Gwo-Yu Chuang, Aliaksandr Druz, Tongqing Zhou, William J Rice, Christoph Wigge, Bridget Carragher, Clinton S Potter, Peter D Kwong, Paolo Lusso
Binding of the gp120 envelope (Env) glycoprotein to the CD4 receptor is the first step in the HIV-1 infectious cycle. Although the CD4-binding site has been extensively characterized, the initial receptor interaction has been difficult to study because of major CD4-induced structural rearrangements. Here we used cryogenic electron microscopy (cryo-EM) to visualize the initial contact of CD4 with the HIV-1 Env trimer at 6.8-Å resolution. A single CD4 molecule is embraced by a quaternary HIV-1-Env surface formed by coalescence of the previously defined CD4-contact region with a second CD4-binding site (CD4-BS2) in the inner domain of a neighboring gp120 protomer...
February 20, 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/28218747/mhc-i-peptides-get-out-of-the-groove-and-enable-a-novel-mechanism-of-hiv-1-escape
#7
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/28218730/neoflavonoids-as-inhibitors-of-hiv-1-replication-by-targeting-the-tat-and-nf-%C3%AE%C2%BAb-pathways
#8
Dionisio A Olmedo, José Luis López-Pérez, Esther Del Olmo, Luis M Bedoya, Rocío Sancho, José Alcamí, Eduardo Muñoz, Arturo San Feliciano, Mahabir P Gupta
Twenty-eight neoflavonoids have been prepared and evaluated in vitro against HIV-1. Antiviral activity was assessed on MT-2 cells infected with viral clones carrying the luciferase reporter gene. Inhibition of HIV transcription and Tat function were tested on cells stably transfected with the HIV-LTR and Tat protein. Seven 4-phenylchromen-2-one derivatives showed HIV transcriptional inhibitory activity but only the phenylchrome-2-one 10 inhibited NF-κB and displayed anti-Tat activity simultaneously. Compounds 10, 14, and 25, inhibited HIV replication in both targets at concentrations <25 μM...
February 19, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28213534/quantitative-correlation-between-infectivity-and-gp120-density-on-hiv-1-virions-revealed-by-optical-trapping-virometry
#9
Michael C DeSantis, Jin H Kim, Hanna Song, Per Johan Klasse, Wei Cheng
No abstract text is available yet for this article.
February 17, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28213514/peripheral-membrane-interactions-boost-the-engagement-by-an-anti-hiv-1-broadly-neutralizing-antibody
#10
Edurne Rujas, José M M Caaveiro, Sara Insausti, Miguel García-Porras, Kouhei Tsumoto, José L Nieva
The 4E10 antibody displays an extreme breadth of HIV-1 neutralization and therefore constitutes a suitable model system for structure- guided vaccine design and immunotherapeutics against AIDS. In this regard, the relevance of auto- reactivity with membrane lipids for the biological function of this antibody is still a subject of controversy. To address this dispute, herein we have compared the membrane-partitioning ability of the 4E10 antibody and several of its variants, which were mutated at the region of the paratope surface in contact with the membrane-interface...
February 17, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28212984/hiv-1-vpr-disrupts-mitochondria-axonal-transport-and-accelerates-neuronal-aging
#11
Ying Wang, Maryline Santerre, Italo Tempera, Kayla Martin, Ruma Mukerjee, Bassel E Sawaya
Disruption of mitochondria axonal transport, essential for the maintenance of synaptic and neuronal integrity and function, has been identified in neurodegenerative diseases. Whether HIV-1 viral proteins affect mitochondria axonal transport is unknown, albeit HIV-associated neurocognitive disorders occur in around half of the patients living with HIV. Therefore, we sought to examine the effect of HIV-1 viral protein R (Vpr) on mitochondria axonal transport. Using mice primary neuronal cultures, we demonstrated that 4-day Vpr treatment reduced the ratio of moving mitochondria associated with (i) less energy (ATP) supply, (ii) reduction in Miro-1 and (iii) increase of α-synuclein which led to loss of microtubule stability as demonstrated by inconsecutive distribution of acetylated α-tubulin along the axons...
February 14, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28212411/lack-of-impact-of-pre-existing-t97a-hiv-1-integrase-mutation-on-integrase-strand-transfer-inhibitor-resistance-and-treatment-outcome
#12
Michael E Abram, Renee R Ram, Nicolas A Margot, Tiffany L Barnes, Kirsten L White, Christian Callebaut, Michael D Miller
T97A is an HIV-1 integrase polymorphism associated with integrase strand transfer inhibitor (INSTI) resistance. Using pooled data from 16 clinical studies, we investigated the prevalence of T97A (pre-existing and emergent) and its impact on INSTI susceptibility and treatment response in INSTI-naive patients who enrolled on elvitegravir (EVG)- or raltegravir (RAL)-based regimens. Prior to INSTI-based therapy, primary INSTI resistance-associated mutations (RAMs) were absent and T97A pre-existed infrequently (1...
2017: PloS One
https://www.readbyqxmd.com/read/28212307/antiretroviral-treatment-in-hiv-1-positive-mothers-neurological-implications-in-virus-free-children
#13
REVIEW
Antonio Victor Campos Coelho, Paola Maura Tricarico, Fulvio Celsi, Sergio Crovella
Since the worldwide introduction of antiretroviral therapy (ART) in human immunodeficiency virus type 1, HIV-1-positive mothers, together with HIV-1 testing prior to pregnancy, caesarian birth and breastfeeding cessation with replacement feeding, a reduction of HIV-1 mother-to-child transmission (MTCT) has been observed in the last few years. As such, an increasing number of children are being exposed in utero to ART. Several questions have arisen concerning the neurological effects of ART exposure in utero, considering the potential effect of antiretroviral drugs on the central nervous system, a structure which is in continuous development in the fetus and characterized by great plasticity...
February 15, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28212298/prevalence-and-clinical-impact-of-human-pegivirus-1-infection-in-hiv-1-infected-individuals-in-yunnan-china
#14
Zhijiang Miao, Li Gao, Yindi Song, Ming Yang, Mi Zhang, Jincheng Lou, Yue Zhao, Xicheng Wang, Yue Feng, Xingqi Dong, Xueshan Xia
Human Pegivirus-1 (HPgV-1) may have a beneficial impact on disease progression in human immunodeficiency virus-1 (HIV-1) infection. However, analysis of the genotypic diversity of HPgV-1 and its relevance to the progression of HIV-1 disease remains limited. A total of 1062 HIV-1-infected individuals were recruited in all sixteen prefectures of Yunnan province, China. The reverse transcription nested polymerase chain reaction (RT-nPCR), phylogenetic analyses, and clinical data analyses were used to detect HPgV-1 infection, determine genotype, and analyze HPgV-1 genotype impact on HIV-1 disease progression...
February 15, 2017: Viruses
https://www.readbyqxmd.com/read/28211951/semiparametric-regression-analysis-of-interval-censored-competing-risks-data
#15
Lu Mao, Dan-Yu Lin, Donglin Zeng
Interval-censored competing risks data arise when each study subject may experience an event or failure from one of several causes and the failure time is not observed directly but rather is known to lie in an interval between two examinations. We formulate the effects of possibly time-varying (external) covariates on the cumulative incidence or sub-distribution function of competing risks (i.e., the marginal probability of failure from a specific cause) through a broad class of semiparametric regression models that captures both proportional and non-proportional hazards structures for the sub-distribution...
February 17, 2017: Biometrics
https://www.readbyqxmd.com/read/28211903/activating-killer-immunoglobulin-receptors-and-hla-c-a-successful-combination-providing-hiv-1-control
#16
Mauro S Malnati, Elisabetta Ugolotti, Maria Cristina Monti, Davide De Battista, Irene Vanni, Domenico Bordo, Francesca Sironi, Patrizia Larghero, Eddi Di Marco, Priscilla Biswas, Guido Poli, Elisa Vicenzi, Agostino Riva, Maciej Tarkowski, Giuseppe Tambussi, Silvia Nozza, Gino Tripodi, Francesco Marras, Andrea De Maria, Angela Pistorio, Roberto Biassoni
Several studies demonstrated a relevant role of polymorphisms located within the HLA-B and -C loci and the Killer Immunoglobulin Receptors (KIRs) 3DL1 and 3DS1 in controlling HIV-1 replication. KIRs are regulatory receptors expressed at the surface of NK and CD8+ T-cells that specifically bind HLA-A and -B alleles belonging to the Bw4 supratype and all the -C alleles expressing the C1 or C2 supratype. We here disclose a novel signature associated with the Elite Controller but not with the long-term nonprogressor status concerning 2DS activating KIRs and HLA-C2 alleles insensitive to miRNA148a regulation...
February 13, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28210927/efficacy-and-safety-of-daclatasvir-plus-pegylated-interferon-alfa-2a-and-ribavirin-in-previously-untreated-hcv-subjects-coinfected-with-hiv-and-hcv-genotype-1-a-phase-iii-open-label-study
#17
Mark S Sulkowski, Walford J Fessel, Adriano Lazzarin, Juan Berenguer, Natalia Zakharova, Hugo Cheinquer, Pierre Côté, Douglas Dieterich, Adrian Gadano, Gail Matthews, Jean-Michel Molina, Christophe Moreno, Juan Antonio Pineda, Federico Pulido, Antonio Rivero, Jurgen Rockstroh, Dennis Hernandez, Fiona McPhee, Timothy Eley, Zhaohui Liu, Patricia Mendez, Eric Hughes, Stephanie Noviello, Peter Ackerman
BACKGROUND: Daclatasvir (DCV) is a potent, pangenotypic, hepatitis C virus (HCV) non-structural protein 5A inhibitor with low potential for drug interactions with antiretroviral therapy (ART). We evaluated the safety and efficacy of DCV plus peginterferon alfa-2a/ribavirin (PegIFN/RBV) in HIV-1/HCV genotype-1-coinfected patients. METHODS: AI444043 (NCT01471574), an open-label, Phase III, single-arm, response-guided treatment (RGT) study included 301 patients. They received DCV doses of 30, 60 or 90 mg once daily (depending on concomitant ART), plus weight-based RBV (<75 kg, 1000 mg/day; or ≥75 kg, 1200 mg/day), and once-weekly PegIFN 180 μg, for 24 weeks...
February 16, 2017: Hepatology International
https://www.readbyqxmd.com/read/28209198/distribution-and-fate-of-hiv-1-unintegrated-dna-species-a-comprehensive-update
#18
REVIEW
Faysal Bin Hamid, Jinsun Kim, Cha-Gyun Shin
Reverse transcription of viral RNA and the subsequent integration of reverse transcripts are the classical early events of the HIV-1 life-cycle. Simultaneously, abundant unintegrated DNAs (uDNAs), are formed in cells ubiquitously. The uDNAs either undergo recombination or degradation or persist inactively for long periods in the nucleus as future resources. Among them, 2-LTR circles are considered a dead-end for viral spread. Their contribution to the HIV-1 infection is still poorly understood. Nevertheless, the preintegration transcription of the aberrant DNAs and the consequent alterations of cellular factors have already been reported...
February 16, 2017: AIDS Research and Therapy
https://www.readbyqxmd.com/read/28209172/evaluation-of-the-contribution-of-the-transmembrane-region-to-the-ectodomain-conformation-of-the-human-immunodeficiency-virus-hiv-1-envelope-glycoprotein
#19
Hanh T Nguyen, Navid Madani, Haitao Ding, Emerald Elder, Amy Princiotto, Christopher Gu, Patrice Darby, James Alin, Alon Herschhorn, John C Kappes, Youdong Mao, Joseph G Sodroski
BACKGROUND: The human immunodeficiency virus (HIV-1) envelope glycoprotein (Env), a Type 1 transmembrane protein, assembles into a trimeric spike complex that mediates virus entry into host cells. The high potential energy of the metastable, unliganded Env trimer is maintained by multiple non-covalent contacts among the gp120 exterior and gp41 transmembrane Env subunits. Structural studies suggest that the gp41 transmembrane region forms a left-handed coiled coil that contributes to the Env trimer interprotomer contacts...
February 16, 2017: Virology Journal
https://www.readbyqxmd.com/read/28208588/depicting-binding-mediated-translocation-of-hiv-1-tat-peptides-in-living-cells-with-nanoscale-pens-of-tat-conjugated-quantum-dots
#20
Chien Y Lin, Jung Y Huang, Leu-Wei Lo
Cell-penetrating peptides (CPPs) can translocate across cell membranes, and thus have great potential for the cellular delivery of macromolecular cargoes. However, the mechanism of this cellular uptake process is not yet fully understood. In this study, a time-lapse single-particle light-sheet microscopy technique was implemented to obtain a parallel visualization of the translocating process of individual human immunodeficiency virus 1 (HIV-1) transactivator of transcription (Tat) peptide conjugated quantum dots (TatP-QDs) in complex cellular terrains...
February 10, 2017: Sensors
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