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HIV-1 Transmission in Switzerland: viral transmission traits, superinfection and drug resistance

English title HIV-1 Transmission in Switzerland: viral transmission traits, superinfection and drug resistance
Applicant Günthard Huldrych Fritz
Number 159868
Funding scheme Project funding (special)
Research institution Klinik für Infektionskrankheiten und Spitalhygiene Universitätsspital Zürich
Institution of higher education University of Zurich - ZH
Main discipline Medical Microbiology
Start/End 01.05.2015 - 30.04.2018
Approved amount 834'000.00
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Keywords (15)

33CS30_148522; Swiss HIV Cohort Study (SHCS); large nested project; viral variants; viral sequence traits; viral set-point; primary HIV infection; large nested project; 33CS30_148522; envelope; HIV-1; transmission; phylogeny; transmitter founder; Swiss HIV Cohort Study (SHCS)

Lay Summary (German)

Lead
Dieses Projekt will helfen, die Biologie von übertragenen HIV-1 Viren besser verstehen. Deshalb werden Viren von Individuen studiert, die diese an einen anderen Menschen weitergeben und zusätzlich wollen wir systematisch untersuchen, weshalb und wie häufig Superinfektion auftreten kann. Schliesslich werden wir die Uebertragung von resistenten HI-Viren studieren und v. a. auf nicht-B Subtypen fokussieren. Die Studie basiert auf zwei qualitativ hochstehenden longitudinalen Patientenstudien: der Schweizerischen HIV Kohortenstudie und der Zurich Primary HIV Infection Study.
Lay summary

Mit diesem Projekt wollen wir bestimmte Charakteristika der HIV-1 Infektion besser verstehen. Im 1. Teil wollen wir herausfinden, ob übertragene Viren spezielle genetische oder phänotypische Merkmale aufweisen. Oder in anderen Worten: Wir möchten studieren, ob Virus-Varianten, die übertragen werden bestimmte genetische oder biologische "Verhaltensmerkmale" aufweisen. Im 2. Teil wollen wir systematisch untersuchen, wie häufig HIV Superinfektionen (SI) auftreten  und welches die Risikofaktoren dafür sind. Bisher gibt es kaum systematische Studien zur Häufigkeit von Superinfektionen und deren Risikofaktoren in repräsentativen Populationen von HIV-1 infizierten Menschen. Bisher haben wir 150-312 potentielle SI Fälle identifizert. Diese werden wir mittels einer detaillierten virusgenetischen Analyse bestätigen und Rekombination und Risikofaktoren bestimmen. Wir werden auch Wirtsgenome analysieren, um zu schauen, ob allenfalls menschliche genetische Faktoren dafür mitverantwortlich sind. Zusätlich werden wir die virale Fitness und neutralisierende Antikörper bestimmen in den Patienten und die "viral setpoints" (virus equilibrium in Patienten vor Therapie) bestimmen in den SI Fällen und ausgewählten kontrollen, um zu testen, ob SI Individuen eine raschere Krankheitsprogression aufweisen. Im 3. Teil werden wir die Uebertragung von resistenten HIV-1 Viren untersuchen. Wir werden uns speziell auf Nicht-B Subtypen und auf neuere Medikamentenklassen konzentrieren. Zusätzlich wollen wir die Reversionsrate von pbertragenen resistenten Viren studieren, was uns Hinweise geben wird auf die "Fitnesskosten" welche diese Resistenzmutationen verursachen.

Direct link to Lay Summary Last update: 25.03.2015

Responsible applicant and co-applicants

Employees

Publications

Publication
Predicting HIV-1 transmission and antibody neutralization efficacy in vivo from stoichiometric parameters
Brandenberg Oliver F., Magnus Carsten, Rusert Peter, Guenthard Huldrych F., Regoes Roland R., Trkola Alexandra (2017), Predicting HIV-1 transmission and antibody neutralization efficacy in vivo from stoichiometric parameters, in PLOS PATHOGENS, 13(5), 1.
Parent-offspring regression to estimate the heritability of an HIV-1 trait in a realistic setup
Bachmann Nadine, Turk Teja, Kadelka Claus, Marzel Alex, Shilaih Mohaned, Boni Jurg, Aubert Vincent, Klimkait Thomas, Leventhal Gabriel E., Gunthard Huldrych F., Kouyos Roger (2017), Parent-offspring regression to estimate the heritability of an HIV-1 trait in a realistic setup, in RETROVIROLOGY, 14, 1.
Evaluation of the Predictive Potential of the Short Acute Retroviral Syndrome Severity Score for HIV-1 Disease Progression in Individuals With Acute HIV Infection
Hoenigl Martin, Braun Dominique L., Kouyos Roger, Guenthard Huldrych F., Little Susan J. (2017), Evaluation of the Predictive Potential of the Short Acute Retroviral Syndrome Severity Score for HIV-1 Disease Progression in Individuals With Acute HIV Infection, in JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES, 74(4), 114-117.
Prescription of Postexposure Prophylaxis for HIV-1 in the Emergency Room: Correct Transmission Risk Assessment Remains Challenging
Marzel Alex, Heinrich Henriette, Schilliger Lukas, Fehr Jan S., Guenthard Huldrych F., Kouyos Roger, Rampini Silvana K. (2017), Prescription of Postexposure Prophylaxis for HIV-1 in the Emergency Room: Correct Transmission Risk Assessment Remains Challenging, in JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES, 74(4), 359-366.
Phylodynamics on local sexual contact networks
Rasmussen David A., Kouyos Roger, Gunthard Huldrych F., Stadler Tanja (2017), Phylodynamics on local sexual contact networks, in PLOS COMPUTATIONAL BIOLOGY, 13(3), 1.
Factors associated with syphilis incidence in the HIV-infected in the era of highly active antiretrovirals
Shilaih Mohaned, Marzel Alex, Braun Dominique L., Scherrer Alexandra U., Kovari Helen, Young Jim, Calmy Alexandra, Darling Katharine, Battegay Manuel, Hoffmann Matthias, Bernasconi Enos, Thurnheer Maria C., Gunthard Huldrych F., Kouyos Roger D. (2017), Factors associated with syphilis incidence in the HIV-infected in the era of highly active antiretrovirals, in MEDICINE, 96(2), 1.
HIV-1 Subtype C, Tenofovir, and the Relationship With Treatment Failure and Drug Resistance.
Günthard Huldrych F, Scherrer Alexandra U (2016), HIV-1 Subtype C, Tenofovir, and the Relationship With Treatment Failure and Drug Resistance., 214(9), 1289-1291, Oxford Academic, UK 214(9), 1289-1291.
A Direct Comparison of Two Densely Sampled HIV Epidemics: The UK and Switzerland
Ragonnet-Cronin Manon L., Shilaih Mohaned, Gunthard Huldrych F., Hodcroft Emma B., Boni Jurg, Fearnhill Esther, Dunn David, Yerly Sabine, Klimkait Thomas, Aubert Vincent, Yang Wan-Lin, Brown Alison E., Lycett Samantha J., Kouyos Roger, Brown Andrew J. Leigh (2016), A Direct Comparison of Two Densely Sampled HIV Epidemics: The UK and Switzerland, in SCIENTIFIC REPORTS, 6, 1.
Tracing HIV-1 transmission: envelope traits of HIV-1 transmitter and recipient pairs
Oberle Corinna S., Joos Beda, Rusert Peter, Campbell Nottania K., Beauparlant David, Kuster Herbert, Weber Jacqueline, Schenkel Corinne D., Scherrer Alexandra U., Magnus Carsten, Kouyos Roger, Rieder Philip, Niederost Barbara, Braun Dominique L., Pavlovic Jovan, Boni Jurg, Yerly Sabine, Klimkait Thomas, Aubert Vincent, Trkola Alexandra, Metzner Karin J., Gunthard Huldrych F. (2016), Tracing HIV-1 transmission: envelope traits of HIV-1 transmitter and recipient pairs, in RETROVIROLOGY, 13, 1.
Successful Prevention of Transmission of Integrase Resistance in the Swiss HIV Cohort Study
Scherrer Alexandra U., Yang Wan-Lin, Kouyos Roger D., Boni Jurg, Yerly Sabine, Klimkait Thomas, Aubert Vincent, Cavassini Matthias, Battegay Manuel, Hauser Christoph, Calmy Alexandra, Schmid Patrick, Bernasconi Enos, Gunthard Huldrych F. (2016), Successful Prevention of Transmission of Integrase Resistance in the Swiss HIV Cohort Study, in JOURNAL OF INFECTIOUS DISEASES, 214(3), 399-402.
Emergence of Acquired HIV-1 Drug Resistance Almost Stopped in Switzerland: A 15-Year Prospective Cohort Analysis
Scherrer Alexandra U., von Wyl Viktor, Yang Wan-Lin, Kouyos Roger D., Boni Jurg, Yerly Sabine, Klimkait Thomas, Aubert Vincent, Cavassini Matthias, Battegay Manuel, Furrer Hansjakob, Calmy Alexandra, Vernazza Pietro, Bernasconi Enos, Gunthard Huldrych F. (2016), Emergence of Acquired HIV-1 Drug Resistance Almost Stopped in Switzerland: A 15-Year Prospective Cohort Analysis, in CLINICAL INFECTIOUS DISEASES, 62(10), 1310-1317.
Contribution of APOBEC3G/F activity to the development of low-abundance drug-resistant human immunodeficiency virus type I variants
Noguera-Julian M., Cozzi-Lepri A., Di Giallonardo F., Schuurman R., Daumer M., Aitken S., Ceccherini-Silberstein F., Monforte A. D'Arminio, Geretti A. M., Booth C. L., Kaiser R., Michalik C., Jansen K., Masquelier B., Bellecave P., Kouyos R. D., Castro E., Furrer H., Schultze A., Guenthard H. F., Brun-Vezinet F., Metzner K. J., Paredes R. (2016), Contribution of APOBEC3G/F activity to the development of low-abundance drug-resistant human immunodeficiency virus type I variants, in CLINICAL MICROBIOLOGY AND INFECTION, 22(2), 191-200.
Assessment of Overlap of Phylogenetic Transmission Clusters and Communities in Simple Sexual Contact Networks: Applications to HIV-1
Villandre Luc, Stephens David A., Labbe Aurelie, Guenthard Huldrych F., Kouyos Roger, Stadler Tanja (2016), Assessment of Overlap of Phylogenetic Transmission Clusters and Communities in Simple Sexual Contact Networks: Applications to HIV-1, in PLOS ONE, 11(2), 1.
Large-scale inference of conjunctive Bayesian networks
Montazeri H Kuipers J Kouyos RD Böni J Yerly S Klimkait T Aubert V Günthard HF (2016), Large-scale inference of conjunctive Bayesian networks, in Bioinformatics, i727.
HIV-1 Transmission During Recent Infection and During Treatment Interruptions as Major Drivers of New Infections in the Swiss HIV Cohort Study
Marzel Alex, Shilaih Mohaned, Yang Wan-Lin, Boeni Juerg, Yerly Sabine, Klimkait Thomas, Aubert Vincent, Braun Dominique L., Calmy Alexandra, Furrer Hansjakob, Cavassini Matthias, Battegay Manuel, Vernazza Pietro L., Bernasconi Enos, Guenthard Huldrych F., Kouyos Roger D. (2015), HIV-1 Transmission During Recent Infection and During Treatment Interruptions as Major Drivers of New Infections in the Swiss HIV Cohort Study, in CLINICAL INFECTIOUS DISEASES, 62(1), 115-122.
Assessing efficacy of different nucleos(t)ide backbones in NNRTI-containing regimens in the Swiss HIV Cohort Study
Yang Wan-Lin, Kouyos Roger D., Scherrer Alexandra U., Boeni Juerg, Shah Cyril, Yerly Sabine, Klimkait Thomas, Aubert Vincent, Hirzel Cedric, Battegay Manuel, Cavassini Matthias, Bernasconi Enos, Vernazza Pietro, Held Leonhard, Ledergerber Bruno, Guenthard Huldrych F. (2015), Assessing efficacy of different nucleos(t)ide backbones in NNRTI-containing regimens in the Swiss HIV Cohort Study, in JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY, 70(12), 3323-3331.
Estimating the dynamics and dependencies of accumulating mutations with applications to HIV drug resistance
Montazeri Hesam, Guenthard Huldrych F., Yang Wan-Lin, Kouyos Roger, Beerenwinkel Niko (2015), Estimating the dynamics and dependencies of accumulating mutations with applications to HIV drug resistance, in BIOSTATISTICS, 16(4), 713-726.
Frequency and Spectrum of Unexpected Clinical Manifestations of Primary HIV-1 Infection
Braun Dominique L., Kouyos Roger D., Balmer Belinda, Grube Christina, Weber Rainer, Guenthard Huldrych F. (2015), Frequency and Spectrum of Unexpected Clinical Manifestations of Primary HIV-1 Infection, in CLINICAL INFECTIOUS DISEASES, 61(6), 1013-1021.
The impact of vaccination on the breadth and magnitude of the antibody response to influenza A viruses in HIV-infected individuals
Kohler Ines, Kouyos Roger, Bianchi Matteo, Grube Christina, Wyrzucki Arkadiusz, Guenthard Huldrych F., Hangartner Lars (2015), The impact of vaccination on the breadth and magnitude of the antibody response to influenza A viruses in HIV-infected individuals, in AIDS, 29(14), 1803-1810.
The Irreversibility of HIV Drug Resistance
Kouyos Roger D., Guenthard Huldrych F. (2015), The Irreversibility of HIV Drug Resistance, 61(5), 837-839, Oxford Academic, UK 61(5), 837-839.
Increases in condomless sex i the Swiss HIV Cohort Study
Kouyos R Hasse B Calmy A Cavassini M Furrer H Stöckle M Vernazza PL Bernasconi E Weber R Gü (2015), Increases in condomless sex i the Swiss HIV Cohort Study, in Open Forum Infectious Diseases, 1.

Collaboration

Group / person Country
Types of collaboration
Prof. Jacques Fellay, EPFL Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Alexandra Trkola, University of Zurich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
Dr. Roger Kouyos, University Hospital Zurich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
Prof. Niko Beerenwinkel, ETHZ, BSSE Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel
Prof. Karin Metzner, University Hospital Zurich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
The Swiss HIV Cohort Study Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
Prof. Volker Roth, University of Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Associated projects

Number Title Start Funding scheme
148522 Swiss HIV Cohort Study (SHCS) 01.01.2014 Cohort Studies Large
146331 HIV-1 whole-genome quasispecies analysis in longitudinal clinical samples 01.04.2013 Interdisciplinary projects
130865 HIV-1 Transmission in Switzerland: Long term-molecular epidemiology and biological properties of transmitted viruses 01.11.2010 Project funding (special)
130865 HIV-1 Transmission in Switzerland: Long term-molecular epidemiology and biological properties of transmitted viruses 01.11.2010 Project funding (special)
179571 HIV-1 Transmission in Switzerland: viral transmission traits, superinfection and drug resistance 01.05.2018 Project funding (special)

Abstract

This translational research project is a continuation of SNF 130865. We aim to unravel traits of HIV transmission in three conceptually different situations of high clinical relevance: transmission leading to de novo infection (Aim 1), spread of HIV between infected individuals (conferred to as superinfection (SI); Aim 2) and transmission of drug resistant virus (Aim 3). The proposed studies are based on two renowned longitudinal studies with extensive biobanks: The Swiss HIV Cohort and the Zurich Primary HIV-1 infection study (ZPHI). AIM 1. Here we will determine whether specific genotypic and phenotypic viral traits of transmitted/founder viruses (T/F) exist. Characterization of T/F viruses, the earliest virus population that emerges in a newly infected individual, is of high interest as understanding their transmis-sion pathways may open avenues for prophylaxis and treatment. Current data on T/F virus features led to intriguing in-sights, but no definitive picture of genetic and phenotypic traits of T/F viruses has emerged. A limitation of previous studies was that features of T/F viruses had to be compared to unrelated viruses from chronically infected patients as transmitting individuals were in most cases not identified. Here using phylogenetically linked T/F viruses and their transmitters we will be able to study phylogenetically linked transmitter-recipient pairs. Thus far we identified 79 acutely HIV infected (recipients) and 107 chronically infected individuals with genetically related HIV strains which are their likely transmitters. Plasma samples close to estimated time of infection will be chosen for virus genomic analysis from transmitters and recipients to retrieve full length HIV-genomes employing Next Generation Sequencing (NGS) followed by haplotype reconstruction. T/F virus will be compared to variants present in the transmitter regarding, length, specific mutations, deletions/insertions, glycosylation sites, charge and frequency to define whether stochastic or non-stochastic transmission occurs. If genotypic traits are identified, gene transfer and mutagenesis experiments will be performed followed by phenotypic analysis to discern if indeed signifying characteristics of T/F viruses exist. To this end we will compare transmitter and T/F viruses for features implicated in shaping transmission including replication capacity, sensitivity to neutralizing antibodies and entry inhibitors, entry kinetics and interferon sensitivity. AIM 2: Here we will systematically explore frequency and risk factors for HIV-1 superinfection in the SHCS and ZPHI. A first phylogenetic screen based on pol sequences has revealed 150-312 potential SI cases. By retrieving longitudinal plasma samples before patients went on antiretroviral therapy we will seek to confirm SI by full length NGS and define approximate time points of SI events. In a detailed virus genomic analysis we aim to reconstruct haplotypes, study recombination events. A specific emphasis of our studies is on determining risk factors for acquiring SI using detailed patient, disease and host genomic data available. Viral fitness of initial circulating and superinfecting strains will be computed using machine learning techniques. To test whether SI is prevented by neutralizing antibody responses, those will be compared among superinfected and non-superinfected individuals. Finally, viral setpoint of cases and controls will be compared to determine the impact of SI on disease progression. AIM 3: Here we will investigate transmission of HIV-1 drug resistance mutations (TDR) within the SHCS, specifically focussing on the non-B compared to the subtype B epidemic, newer drugs, and reversion rates of TDR. We will study TDR prevalence over time for B and non- B subtypes in all drug naives and, specifically, in recently infected individuals. We will particularly focus on newer drugs. In patients with TDR we will determine reversion rates for specific TDR and fitness cost by taking into account the pol genotypic backbone indepen-dently of TDR. Furthermore, by performing phylogenetic analysis we will study whether there are differences in transmission dynamics between B- and non-B subtype TDR. This analysis will reveal whether TDR in the non-B subtypes is increasing as would be expected due to the recent, wide spread roll out of antiretroviral drugs in developing countries.
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