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HIV genomics

Daniel M Lyons, Adam S Lauring
The substitution rates of transitions are higher than expected by chance relative to those of transversions. Many have argued that selection disfavors transversions, as nonsynonymous transversions are less likely to conserve biochemical properties of the original amino acid. Only recently has it become feasible to directly test this selective hypothesis by comparing the fitness effects of a large number of transition and transversion mutations. For example, a recent study of six viruses and one beta-lactamase gene did not find evidence supporting the selective hypothesis...
September 25, 2017: Molecular Biology and Evolution
François E Dufrasne, Mara Lucchetti, Anandi Martin, Emmanuel André, Géraldine Dessilly, Benoit Kabamba, Patrick Goubau, Jean Ruelle
The HIVs have evolved by selecting means to hijack numerous host cellular factors. HIVs exploit the transcription factor NF-κB to ensure efficient LTR-driven gene transcription. However, NF-κB is primarily known to act as a key regulator of the proinflammatory and antiviral responses. Interestingly, retroviruses activate NF-κB during early stages of infection to initiate proviral genome expression while suppressing it at later stages to restrain expression of antiviral genes. During HIV-1 infection, diverse viral proteins such as Env, Nef and Vpr have been proposed to activate NF-κB activity, whereas Vpu has been shown to inhibit NF-κB activation...
October 10, 2017: Virology
Sylvia Kiwuwa-Muyingo, Jamirah Nazziwa, Deogratius Ssemwanga, Pauliina Ilmonen, Harr Njai, Nicaise Ndembi, Chris Parry, Paul Kato Kitandwe, Asiki Gershim, Juliet Mpendo, Leslie Neilsen, Janet Seeley, Heikki Seppälä, Fred Lyagoba, Anatoli Kamali, Pontiano Kaleebu
BACKGROUND: Fishing communities around Lake Victoria in sub-Saharan Africa have been characterised as a population at high risk of HIV-infection. METHODS: Using data from a cohort of HIV-positive individuals aged 13-49 years, enrolled from 5 fishing communities on Lake Victoria between 2009-2011, we sought to identify factors contributing to the epidemic and to understand the underlying structure of HIV transmission networks. Clinical and socio-demographic data were combined with HIV-1 phylogenetic analyses...
2017: PloS One
Joanna Peters, Fiona Cresswell, Lauren Amor, Kevin Cole, Gillian Dean, Xavier Didelot, Dilrini De Silva, David W Eyre, John Paul
OBJECTIVES: Prevention and control of gonorrhoea depends on understanding the nature of sexual networks and risk factors for infection. We aimed to use high-resolution typing (whole genome sequencing (WGS)) of Neisseria gonorrhoeae isolates plus patient questionnaire data to gain insights into transmission patterns in a high prevalence setting. METHODS: During a 9-month period (July 2014-March 2015), patients diagnosed with gonorrhoea attending sexual health service in Brighton, UK, were invited to provide anonymised detailed information by questionnaire about risk factors for infection...
October 11, 2017: Sexually Transmitted Infections
Vicente Soriano
The huge success of current antiretroviral therapy is mediated by a triple effect: (i) Halting progression to AIDS in infected persons; (ii) reducing the risk of transmission to contacts (treatment as prevention); and (iii) minimizing the risk of HIV acquisition treating uninfected persons at risk (pre-exposure prophylaxis). However, UNAIDS has estimated that only 70% of infected people globally are diagnosed, only 53% are treated, and overall 44% have undetectable viral load, which is the necessary request for ensuring any antiretroviral benefit...
October 11, 2017: AIDS Reviews
Donglai Liu, Chu Wang, Bhavna Hora, Tao Zuo, Nilu Goonetilleke, Michael K P Liu, Mark Berrong, Guido Ferrari, Andrew J McMichael, Tanmoy Bhattacharya, Alan S Perelson, Feng Gao
BACKGROUND: Mutations rapidly accumulate in the HIV-1 genome after infection. Some of those mutations are selected by host immune responses and often cause viral fitness losses. This study is to investigate whether strongly selected mutations that are not associated with immune responses result in fitness losses. RESULTS: Strongly selected mutations were identified by analyzing 5'-half HIV-1 genome (gag/pol) sequences from longitudinal samples of subject CH0131...
October 10, 2017: Retrovirology
M Neary, A Owen
Variations in the human genome sequence sometimes play an important role in pharmacokinetics and/or pharmacodynamics. Previous studies have demonstrated a high degree of variation both between and within different ethnic populations. Areas Covered: This review sought to summarise key SNPs in CYP2B6, CYP3A enzymes, CYP2C enzymes, UGT2 enzymes, ABCB1, ABCC2, SLCO1B1, NR1I2 and NR1I3 that have previously been associated with variability in antiretroviral pharmacokinetics. Additionally, the impact of ethnicity in these pharmacogenetics studies is discussed and variation in findings between different ethnic groups is reviewed...
October 10, 2017: Expert Opinion on Drug Metabolism & Toxicology
Yoko Takiuchi, Masayuki Kobayashi, Kohei Tada, Fumie Iwai, Maki Sakurada, Shigeki Hirabayashi, Kayoko Nagata, Kotaro Shirakawa, Keisuke Shindo, Jun-Ichirou Yasunaga, Yasuhiro Murakawa, Vinodh Rajapakse, Yves Pommier, Masao Matsuoka, Akifumi Takaori-Kondo
Adult T-cell leukemia (ATL) is an aggressive T-cell malignancy caused by human T-cell leukemia virus type 1 (HTLV-1). We recently reported that abacavir, an anti-HIV-1 drug, potently and selectively kills ATL cells. This effect was attributed to the reduced expression of tyrosyl-DNA-phosphodiesterase 1 (TDP1), a DNA repair enzyme, in ATL cells. However, the molecular mechanism underlying the downregulation of TDP1 in ATL cells remains elusive. Here we identified the core promoter of the TDP1 gene, which contains a conserved nuclear respiratory factor 1 (NRF-1) binding site...
October 9, 2017: Scientific Reports
Robin van der Lee, Laurens Wiel, Teunis J P van Dam, Martijn A Huynen
Hotspots of rapid genome evolution hold clues about human adaptation. We present a comparative analysis of nine whole-genome sequenced primates to identify high-confidence targets of positive selection. We find strong statistical evidence for positive selection in 331 protein-coding genes (3%), pinpointing 934 adaptively evolving codons (0.014%). Our new procedure is stringent and reveals substantial artefacts (20% of initial predictions) that have inflated previous estimates. The final 331 positively selected genes (PSG) are strongly enriched for innate and adaptive immunity, secreted and cell membrane proteins (e...
August 11, 2017: Nucleic Acids Research
Gennady G Fedonin, Yury S Fantin, Alexnader V Favorov, German A Shipulin, Alexey D Neverov
Characterization of the within-host genetic diversity of viral pathogens is required for selection of effective treatment of some important viral infections, e.g. HIV, HBV and HCV. Despite the technical ability of detection, there are conflicting data regarding the clinical significance of low-frequency variants, partially because of the difficulty of their distinguishing from experimental artifacts. The issue of cross-contamination is relevant for all highly sensitive techniques, including deep sequencing: even trace contamination leads to a significant increase of false positives in identified SNVs...
July 28, 2017: Briefings in Bioinformatics
Paul J McLaren, Sara L Pulit, Deepti Gurdasani, Istvan Bartha, Patrick R Shea, Cristina Pomilla, Namrata Gupta, Effrossyni Gkrania-Klotsas, Elizabeth H Young, Norbert Bannert, Julia Del Amo, John Gill, Jill Gilmour, Paul Kellam, Anthony D Kelleher, Anders Sönnerborg, Robert Zangerle, Frank A Post, Martin Fisher, David W Haas, Bruce D Walker, Kholoud Porter, David B Goldstein, Manjinder S Sandhu, Paul I W de Bakker, Jacques Fellay
Background: Previous genetic association studies of HIV-1 progression have focused on common human genetic variation ascertained through genome-wide genotyping. Methods: We sought to systematically assess the full spectrum of functional variation in protein coding gene regions on HIV-1 progression through exome sequencing of 1,327 individuals. Genetic variants were tested individually and in aggregate across genes and gene sets for an influence on HIV-1 viral load...
September 9, 2017: Journal of Infectious Diseases
Vadim Puller, Richard Neher, Jan Albert
Estimating the time since infection (TI) in newly diagnosed HIV-1 patients is challenging, but important to understand the epidemiology of the infection. Here we explore the utility of virus diversity estimated by next-generation sequencing (NGS) as novel biomarker by using a recent genome-wide longitudinal dataset obtained from 11 untreated HIV-1-infected patients with known dates of infection. The results were validated on a second dataset from 31 patients. Virus diversity increased linearly with time, particularly at 3rd codon positions, with little inter-patient variation...
October 2017: PLoS Computational Biology
Wataru Nomura
 Interactions between bio-macromolecules such as proteins, DNA, and polysaccharides play pivotal roles in maintaining homeostasis in living systems. For elucidating the function of biomolecules, peptides are powerful tools, compared to native proteins, because of their lower molecular weights, compatibility with chemical modification, and predictability of interaction with the target molecules. These advantages enabled us to develop peptide-based functional molecules. However, for the purposes of controlling or regulating biomolecule functions, designing artificial proteins is also an effective approach...
2017: Yakugaku Zasshi: Journal of the Pharmaceutical Society of Japan
Masako Nomaguchi, Naoya Doi, Takaaki Koma, Akio Adachi
We have constructed two human immunodeficiency type 1 (HIV-1) derivatives, CXCR4 tropic and CCR5 tropic, that replicate in rhesus macaques. They are genetically engineered to be resistant to macaque restriction factors against HIV-1, including TRIM5α, APOBEC3, and tetherin proteins. The two HIV-1 variants described here are fundamental clones aiming for rhesus infection studies of HIV-1.
September 28, 2017: Genome Announcements
Shujie Song, Shasha Gong, Pragya Singh, Jianxin Lyu, Yidong Bai
Mitochondria play important roles in multiple aspects of viral tumorigenesis. Mitochondrial genomes contribute to the host's genetic background. After viruses enter the cell, they modulate mitochondrial function and thus alter bioenergetics and retrograde signaling pathways. At the same time, mitochondria also regulate and mediate viral oncogenesis. In this context, oncogenesis by oncoviruses like Hepatitis B virus (HBV), Hepatitis C virus (HCV), Human papilloma virus (HPV), Human Immunodeficiency virus (HIV) and Epstein-Barr virus (EBV) will be discussed...
September 26, 2017: Biochimica et Biophysica Acta
Kajwal Kumar Patra, Akash Bhattacharya, Swati Bhattacharya
The sterile alpha motif and histidine-aspartate domain-containing protein 1 (or SAMHD1), a human dNTP-triphosphohydrolase, contributes to HIV-1 restriction in select terminally differentiated cells of the immune system. The catalytically active form of the protein is an allosterically triggered tetramer, whose HIV-1 restriction properties are attributed to its dNTP - triphosphohydrolase activity. The tetramer itself is assembled by a GTP/dNTP combination. This enzyme uses the strategy of deoxynucleotide starvation, which is thought to prevent effective reverse transcription of the retroviral genome - hence restricting HIV-1 propagation...
September 28, 2017: Journal of Chemical Information and Modeling
Rodrigo Pessôa, Sabri S Sanabani
BACKGROUND: An improved understanding of the prevalence of low-abundance transmitted drug-resistance mutations (TDRM) in therapy-naïve HIV-1-infected patients may help determine which patients are the best candidates for therapy. In this study, we aimed to obtain a comprehensive picture of the evolving HIV-1 TDRM across the massive parallel sequences (MPS) of the viral entire proviral genome in a well-characterized Brazilian blood donor naïve to antiretroviral drugs. MATERIALS AND METHODS: The MPS data from 128 samples used in the analysis were sourced from Brazilian blood donors and were previously classified by less-sensitive (LS) or "detuned" enzyme immunoassay as non-recent or longstanding HIV-1 infections...
2017: PloS One
Matthew A Takata, Daniel Gonçalves-Carneiro, Trinity M Zang, Steven J Soll, Ashley York, Daniel Blanco-Melo, Paul D Bieniasz
Vertebrate genomes exhibit marked CG suppression-that is, lower than expected numbers of 5'-CG-3' dinucleotides. This feature is likely to be due to C-to-T mutations that have accumulated over hundreds of millions of years, driven by CG-specific DNA methyl transferases and spontaneous methyl-cytosine deamination. Many RNA viruses of vertebrates that are not substrates for DNA methyl transferases mimic the CG suppression of their hosts. This property of viral genomes is unexplained. Here we show, using synonymous mutagenesis, that CG suppression is essential for HIV-1 replication...
October 5, 2017: Nature
Minakshi Prasad, Koushlesh Ranjan, Basanti Brar, Ikbal Shah, Upendra Lalmbe, J Manimegalai, Bhavya Vashisht, Madhusudan Gaury, Pawan Kumar, Sandip Kumar Khurana, Gaya Prasad, Jagveer Rawat, Vikas Yadav, Sunil Kumar, Rekha Rao
Viruses are the most devastating pathogens of almost all life forms including humans and animals. Viruses can replicate very fast and may affect any metabolic and physiological function of the host cell. Therefore, it has been a challenge to develop a universal and common treatment against viral pathogens, in contrast to bacterial pathogens. Virus-host interaction is a complex phenomenon and often is virus- and host cell-specific. Exciting new insights into the molecular pathogenesis and host-virus interactions have been gained over the past few decades...
September 24, 2017: Current Drug Metabolism
Isabelle Malet, Frédéric Subra, Charlotte Charpentier, Gilles Collin, Diane Descamps, Vincent Calvez, Anne-Geneviève Marcelin, Olivier Delelis
Resistance to the integrase strand transfer inhibitors raltegravir and elvitegravir is often due to well-identified mutations in the integrase gene. However, the situation is less clear for patients who fail dolutegravir treatment. Furthermore, most in vitro experiments to select resistance to dolutegravir have resulted in few mutations of the integrase gene. We performed an in vitro dolutegravir resistance selection experiment by using a breakthrough method. First, MT4 cells were infected with human immunodeficiency virus type 1 (HIV-1) Lai...
September 26, 2017: MBio
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