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Virology of HIV, Hep B & Hep C

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HIV, HBV, HCV Virology Anna Maria Geretti Institute of Infection & Global Health University of Liverpool HIV HBV HCV • Many similarities • Several fundamental differences HIV RNA • Chronic infection • Latent reservoir as virus • Without treatment, most integrated provirus people develop AIDS and die • Antiviral therapy controls within ~10 years (7.5 to 11.6)1,2 but does not eradicate HIV • Non-AIDS HIV-related disease • Life-long therapy required to suppress virus replication • PrEP and PEP 1. Todd AIDS 2007; 2. Laskey Nature Rev Microbiol 2014 HBV DNA • Vaccine • Persistence as cccDNA, virus • Chronic infection in >90% may integrate children, <5% adults • Several replicative states • Cirrhosis (~30%) • Antiviral therapy not always • Hepatocellular carcinoma required, controls but does (with/without cirrhosis) not eradicate HBV, can be stopped in some cases • Extra-hepatic disease • Antivirals work as PrEP HCV RNA • Chronic infection ~80% • No stable or latent reservoir virus • Cirrhosis (41% over 30 years), • Curable with antiviral hepatocellular carcinoma therapy • Extra-hepatic disease increasingly recognised1,2 Cytoplasm Nucleus 1. Giordano JAMA 2007; 2. Lee JID 2012 Attachment Fusion Release of RNA Assembly Reverse transcription Integration Transcription Maturation HIV replication & budding Fusion inhibitors CCR5 antagonists Attachment Fusion Release of RNA RT Integrase inhibitors inhibitors ProteaseAssembly Reverse transcription Integration Transcription inhibitors Maturation Targets of therapy & budding Maturation & budding Protease Polyprotein HIV Reverse transcriptase/Polymerase Two mechanisms of inhibition • Competitive – NRTIs • Allosteric – NNRTIs Wright et al. Biology 2012 Primer strand NRTI 5’ DNA chain terminated 3’ 5’ Template strand HIV DNA forms Host cell Nucleus HIV RNA Linear HIV DNA 2-LTRc 1-LTRc Integration Host DNA Proviral DNA HIV RNA Effect of ART duration on virological & immunological parameters LESS MORE sCD14 p=0.19 CD8+HLA-DR+ p=0.17 CD8+CD38+ p=0.01 CD4+CD69+ p=0.22 CD4+CD38+ p=0.01 CD4+CD26+ p=0.69 CD4 count p=0.05 Integrated HIV-1 DNA p=0.28 Total HIV-1 DNA p=0.60 2-LTRc DNA p=0.01 Residual plasma HIV-1 RNA p=0.08 -1.0 -0.8 -0.6 -0.4 -0.2 0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 Mean difference per 10 years of suppressive ART log-transformed variables Mean Change by duration of VLS<50 cps Ruggiero EBiomed 2015 Virus replication resumes if therapy is stopped Effective therapy 100000 1000 HIV RNA in plasma 10 Dec-04 Jun-05 Dec-05 Jun-06 Dec-06 Jun-07 Dec-07 Jun-08 Dec-08 Jun-09 Dec-09 Jun-10 . Antiretroviral therapy cannot achieve HIV eradication . After stopping therapy HIV replication resumes to pre-treatment levels Mechanisms of HIV genetic evolution 1. Errors by viral reverse transcriptase – ~1 mis-incorporation per genome round 2. Errors by cellular RNA polymerase II 3. APOBEC-driven GA hypermutation – Deamination of cytosine residues in nascent DNA 4. Recombination between HIV strains • Rapid replicating virus (~1010 particles/day) • Rapid clearance of newly produced virus • Highly error prone polymerase High mutation rate • Some mutations detrimental, some allow escape Quasispecies rapid turnover Escape rapid adaptation Fitness PCR Viral gene (e.g., RT) HIV RNA Plasma Sequencing Mutations RT M184V Methionine Valine @ codon 184 of RT ATG / AUG GTG / GUG 100 Detected by conventional sequencing 10 Detected by deep 1 sequencing 0.1 Mutation Frequency 0.01 Natural background 0.001 Limit of detection of conventional sequencing 20% - ~10 Emergence & evolution of HIV drug resistance Single mutant Double mutant Triple mutant The genetic barrier to resistance is expression of multiple interacting factors • Virus sequence • Drug potency • Viral load • Phenotypic effect of • Mode of interaction • Host genetics individual mutations between drug and • Host immune • No. of mutations target function required to reduce • Drug • Reservoirs of drug susceptibility concentration replications • Fitness cost of the • Drug combination mutation • Antagonism or • Ease of emergence synergism between of compensatory resistance pathways adjustments More than the sum of each drug in a regimen Mechanisms of NRTI resistance . M184V (3TC, FTC) . T215Y (AZT, ABC, ddI, d4T, TDF) Mechanisms of NRTI resistance . M184V . T215Y Antagonised by M184V Integrase)Inhibitors)and)Dissocia: on)) Dissociation time of integrase inhibitors ) Hightower Antimicrob Agents Chemother 2011; Quashie J Virol 2012; Wainberg ISHEID Conference 2014; Doyle JAC 2015 Integrase)Inhibitors)and)Dissocia: on)) Dissociation time of Replicative capacity of integrase inhibitors ) integrase mutants Hightower Antimicrob Agents Chemother 2011; Quashie J Virol 2012; Wainberg ISHEID Conference 2014; Doyle JAC 2015 Integrase)Inhibitors)and)Dissocia: on)) Dissociation time of Replicative capacity of integrase inhibitors ) integrase mutants GGT or GGC Glycine GGA or GGG Codon usage at integrase position subtype B AGT or AGC non-B subtypes 140 in B vs. non-B Serine subtypes Hightower Antimicrob Agents Chemother 2011; Quashie J Virol 2012; Wainberg ISHEID Conference 2014; Doyle JAC 2015 HBV replication HBV drug targets Nucleoside and nucleotide analogues Lamivudine* Adefovir Entecavir* Telbivudine Tenofovir* Emtricitabine* HCV replication HCV enzymes provide good targets for drug development HCV Replicase HCV enzymes provide good targets Cfor dE1rug E2 p7 NS2 NS3 NS4A NS4B NS5A NS5B development Structural Protease RNA HCV Replicase Polymerase Cleavage NS5B Polymerase C E1 E2 p7 NS2 NS3 NS4A NS4B NS5A NS5B Replicated NS2 HCV RNA Structural P7 NS4B Protease RNA E2 NS3• 4A NS5A HCV replicase PoE1lymerase Protease C NS5B Cleavage NS5B PolymerasHeCV DrAG ResisSS 2012 v.1 9 Adapted from Kwong AD, et al. Curr Opin Pharmacol. 2008; 8(5): 522-31 www.hivforum.org Replicated NS2 HCV RNA P7 NS4B E2 NS3• 4A NS5A HCV replicase E1 Protease C NS5B Brett Nature 2005 HCV DrAG ResisSS 2012 v.1 9 Adapted from Kwong AD, et al. Curr Opin Pharmacol. 2008; 8(5): 522-31 www.hivforum.org HCV drug targets HCV enzymes provide good targets for drug development HCV Replicase HCV enzymes provide good targets Cfor dE1rug E2 p7 NS2 NS3 NS4A NS4B NS5A NS5B development Structural NS5A Protease RNA HCV Replicase Inhibitors Polymerase NS5A Cleavage Inhibitors NS5B Polymerase C E1 E2 p7 NS2 NS3 NS4A NS4B NS5A NS5B Replicated NS2 HCV RNA Structural P7 NS4B Protease RNA E2 NS3• 4A NS5A HCV replicase NS3 PoE1lymerase Protease C NS5B Cleavage Protease Inhibitors NS5B NS5B PolymerasHeCV DrAG ResisSS 2012 v.1 9 Adapted from Kwong AD, et al. Curr Opin Pharmacol. 2008; 8(5): 522-31 www.hivforum.org Replicated Inhibitors NS2 HCV RNA P7 NS4B E2 NS3• 4A NAs and non-NAs NS5A HCV replicase E1 Protease C NS5B HCV DrAG ResisSS 2012 v.1 9 Adapted from Kwong AD, et al. Curr Opin Pharmacol. 2008; 8(5): 522-31 www.hivforum.org • Rapid replicating virus (HIV 1010 - HBV 1011 - HCV 1012 particles/day) • Rapid clearance of newly produced virus • Highly error prone polymerase High mutation rate • Some mutations are detrimental, some allow escape Quasispecies rapid turnover Escape rapid adaptation Fitness HIV HCV HBV Incidence of HBV drug resistance Years 1-5; first-line therapy HCV genetic variability NS3: 42% of amino NS5A: 46% of NS5B: 55% of acid conserved amino acid amino acid among all conserved among conserved among genotypes all genotypes all genotypes Prevalence of NS3 resistance mutations in naïve patients with HCV Gt1a RAMs CS & DS DS >10% 1-10% • HCV treatment-naïve subjects n 238 n 178 • n (%) n (%) Tested by Conventional Sequencing (CS) and Deep 36 M 1 (0.4) 2 (1.1) Sequencing (DS, Illumina) 36 L 5 (2.1) 0 (0) 54 S 9 (3.8) 0 (0) • Most mutations detected by 55 A 10 (4.2) 0 (0) CS (= dominant) 80 K 44 (18.5) 0 (0) • No difference in HCV RNA 168 E 1 (0.4) 0 (0) load in samples with vs. 170 A 1 (0.4) 0 (0) without resistance 170 T 0 (0) 2 (1.1) (= preserved fitness) RAMs = Resistance-associated mutations Beloukas Clin Microbiol Infect 2015 Profile of HCV treatment options TARGET of THERAPY A Protease Protease NS5A NS5B NS5B 1st gen 2nd gen NAs non-NAs Resistance profile Genotype coverage Potency Least favourable profile Average profile Good profile Key points: Drug resistance with HIV, HBV, HCV Drug-resistant mutants emerge ”spontaneously “ during virus replication HIV and HBV mutants exist as rare species prior to therapy HCV single/double mutants are often dominant in naïve patients (NS3 and NS5A) Virus replication under drug pressure drives expansion of the mutants – Natural evolution increasing resistance & fitness If therapy is stopped, drug susceptible virus tends to outgrow resistant mutants selected by therapy – mutants persist as enriched minority species Mutants are archived in HIV DNA provirus and HBV cccDNA Your turn Which of the following correctly describes HIV? 1. RNA virus, high replication during AIDS phase only 2. RNA virus, high replication, stable genetic make-up 3. RNA virus, high replication, rapid genetic evolution Your turn Which of the following correctly describes HIV? 1. RNA virus, high replication during AIDS phase only 2. RNA virus, high replication, stable genetic make-up 3. RNA virus, high replication, rapid genetic evolution Your turn Which of the following correctly describes HBV? 1. HBV polymerase lacks reverse transcriptase activity 2. The genomic structure favours rapid emergence of resistance 3. Resistance is less of a problem with 3rd gen drugs Your turn Which of the following correctly describes HBV? 1. HBV polymerase lacks reverse transcriptase activity 2. The genomic structure favours rapid emergence of resistance 3. Resistance is less of a problem with 3rd gen drugs Your turn Which of the following correctly describes HCV? 1. Resistance is created by suboptimal therapy 2. Resistance is selected by suboptimal therapy 3. Resistance is archived in the nucleus of hepatocytes Your turn Which of the following correctly describes HCV? 1.
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  • Structure and Function of the Influenza a Virus Non-Structural Protein 1 Chang Woo Han1†, Mi Suk Jeong2†, and Se Bok Jang1*

    Structure and Function of the Influenza a Virus Non-Structural Protein 1 Chang Woo Han1†, Mi Suk Jeong2†, and Se Bok Jang1*

    J. Microbiol. Biotechnol. (2019), 29(8), 1184–1192 https://doi.org/10.4014/jmb.1903.03053 Research Article Review jmb Structure and Function of the Influenza A Virus Non-Structural Protein 1 Chang Woo Han1†, Mi Suk Jeong2†, and Se Bok Jang1* 1Department of Molecular Biology, College of Natural Sciences, Pusan National University, Busan 46241, Republic of Korea 2Korea Nanobiotechnology Center, Pusan National University, Busan 46241, Republic of Korea Received: March 25, 2019 Revised: May 27, 2019 The influenza A virus is a highly infectious respiratory pathogen that sickens many people Accepted: June 3, 2019 with respiratory disease annually. To prevent outbreaks of this viral infection, an First published online understanding of the characteristics of virus-host interaction and development of an anti-viral June 4, 2019 agent is urgently needed. The influenza A virus can infect mammalian species including *Corresponding author humans, pigs, horses and seals. Furthermore, this virus can switch hosts and form a novel Phone: +82-51-510-2523; lineage. This so-called zoonotic infection provides an opportunity for virus adaptation to the Fax: +82-51-581-2544; E-mail: [email protected] new host and leads to pandemics. Most influenza A viruses express proteins that antagonize the antiviral defense of the host cell. The non-structural protein 1 (NS1) of the influenza A † These authors contributed virus is the most important viral regulatory factor controlling cellular processes to modulate equally to this work. host cell gene expression and double-stranded RNA (dsRNA)-mediated antiviral response. This review focuses on the influenza A virus NS1 protein and outlines current issues including the life cycle of the influenza A virus, structural characterization of the influenza A virus NS1, interaction between NS1 and host immune response factor, and design of inhibitors resistant pISSN 1017-7825, eISSN 1738-8872 to the influenza A virus.