# Project

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## Acute and chronic dynamics of HIV and HCV infections, within-host evolution and epidemiological outcomes

 Applicant Althaus Christian 136737 Ambizione Institute of Social and Preventive Medicine University of Bern University of Berne - BE Infectious Diseases 01.10.2011 - 30.11.2014 439'722.00
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### All Disciplines (4)

Discipline
 Infectious Diseases
 Medical Microbiology
 Mathematics
 Clinical Immunology and Immunopathology

### Keywords (7)

HIV; HCV; virus dynamics; CD8+ T cell response; immune escape; T-cell-based vaccine; mathematical modeling

### Lay Summary (English)

Lay summary

Human immunodeficiency virus (HIV) and hepatitis C virus (HCV) are potentially fatal chronic virus infections of public health importance. Whereas HCV can be cleared spontaneously in some infected individuals, HIV persists in the host but some patients can maintain long-term control of HIV replication during the chronic phase. The cellular immune response, and in particular the CD8+ T cell response, has been strongly associated to play a role in determining the outcome of both HIV and HCV infections. Nevertheless, there is conflicting evidence on the importance of CD8+ T cells in viral clearance or control and it remains unclear when, how and to what extent the CD8+ T cells interfere with viral replication. Mathematical modeling plays an important role in analyzing and interpreting clinical data of patients infected with HIV or HCV. The first part of this project deals with the analysis of four different data sets that cover particular aspects of HIV and HCV infection during the acute and chronic phase. By studying the viral turnover in different patients that are infected with HIV, and the occurrence of immune escape variants in HCV, the analyses will provide novel and fundamental insights into the viral dynamics and evolution within a host. In the second part, the insights from the data analysis will be used to develop new mathematical models of virus dynamics. This will help to conceptually study the factors that can influence the differential outcomes of HIV and HCV infections and test different hypotheses about the role of CD8+ T cells on the virus dynamics. The third part of the project deals with the evolution and spread of HIV variants that confer escape from CD8+ T cell recognition. Mathematical and computational models will be developed to study the rate at which such escape variants can spread at the population level, thereby anticipating the ongoing HIV epidemic. In summary, this project will provide new insights into how CD8+ T cells shape the viral dynamics and evolution, shedding more light on the controversial issue of the role of CD8+ T cells in suppressing viral replication. Ultimately, the newly gained insights into the role of CD8+ T cells to induce a selection pressure on the virus population, both within a host and at the population level, will be important for ongoing efforts in T-cell-based vaccine design for HIV and HCV.

 Direct link to Lay Summary Last update: 21.02.2013

### Responsible applicant and co-applicants

Name Institute
 Althaus Christian Institute of Social and Preventive Medicine University of Bern

### Employees

Name Institute
 Althaus Christian Institute of Social and Preventive Medicine University of Bern

### Publications

Publication
Althaus Christian Lorenz (2015), Ebola superspreading, in The Lancet Infectious Diseases, 15(5), 507-508.
Althaus C.L., Low N., Musa E.O., Shuaib F., Gsteiger S. (2015), Ebola virus disease outbreak in Nigeria: Transmission dynamics and rapid control, in Epidemics , 11(0), 80-84.
Althaus Christian Lorenz (2015), Of mice, macaques and men: scaling of virus dynamics and immune responses, in Frontiers in Microbiology, 6(355), 1-3.
Kucharski A J, Althaus C L (2015), The role of superspreading in Middle East respiratory syndrome coronavirus (MERS-CoV) transmission., in Euro surveillance : bulletin Européen sur les maladies transmissibles = European communicable diseas, 20(25), 14-18.
Althaus Christian L, Turner Katherine M E, Mercer Catherine H, Auguste Peter, Roberts Tracy E, Bell Gill, Herzog Sereina A, Cassell Jackie A, Edmunds W John, White Peter J, Ward Helen, Low Nicola (2014), Effectiveness and cost-effectiveness of traditional and new partner notification technologies for curable sexually transmitted infections: observational study, systematic reviews and mathematical modelling., in Health technology assessment (Winchester, England), 18(2), 1-100.
Althaus Christian L, Joos Beda, Perelson Alan S, Günthard Huldrych F (2014), Quantifying the turnover of transcriptional subclasses of HIV-1-infected cells., in PLoS computational biology, 10(10), 1003871-1003871.
Low Nicola, Heijne Janneke Cornelia Maria, Herzog Sereina Annik, Althaus Christian Lorenz (2014), Reinfection by untreated partners of people treated for Chlamydia trachomatis and Neisseria gonorrhoeae: mathematical modelling study., in Sexually transmitted infections, 1.
Heijne Janneke C M, Herzog Sereina A, Althaus Christian L, Low Nicola, Kretzschmar Mirjam (2013), Case and partnership reproduction numbers for a curable sexually transmitted infection., in Journal of theoretical biology, 331, 38-47.
Herzog Sereina A, Heijne Janneke C M, Scott Pippa, Althaus Christian L, Low Nicola (2013), Direct and indirect effects of screening for Chlamydia trachomatis on the prevention of pelvic inflammatory disease: a mathematical modeling study., in Epidemiology (Cambridge, Mass.), 24(6), 854-62.
Heijne Janneke Cornelia Maria, Herzog Sereina Annik, Althaus Christian Lorenz, Tao Guoyu, Kent Charlotte Kathleen, Low Nicola (2013), Insights into the timing of repeated testing after treatment for Chlamydia trachomatis: data and modelling study., in Sexually transmitted infections, 89(1), 57-62.
Althaus Christian, Estimating the Reproduction Number of Ebola Virus (EBOV) During the 2014 Outbreak in West Africa, in PLOS Currents: Outbreaks.
Althaus Christian L., Salathé Marcel, Measles Vaccination Coverage and Cases among Vaccinated Persons, in Emerg Infect Dis, 21(8).

### Collaboration

Group / person Country
Types of collaboration
 Alan Perelson, Los Alamos National Laboratory United States of America (North America)
 - in-depth/constructive exchanges on approaches, methods or results- Publication
 Huldrych Günthard, University Hospital Zurich Switzerland (Europe)
 - in-depth/constructive exchanges on approaches, methods or results- Publication
 Andri Rauch, University Hospital Bern and University of Bern Switzerland (Europe)
 - in-depth/constructive exchanges on approaches, methods or results
 Catherine Mercer, University College London Great Britain and Northern Ireland (Europe)
 - in-depth/constructive exchanges on approaches, methods or results- Publication

### Scientific events

#### Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
 European Scientific Conference on Applied Infectious Disease Epidemiology (ESCAIDE) Talk given at a conference Ebola virus disease outbreak in Nigeria: lessons to learn 05.11.2014 Stockholm, Sweden Althaus Christian;
 Fifth International Meeting on Emerging Diseases and Surveillance (IMED 2014) Talk given at a conference Ebola virus disease outbreak in Nigeria: lessons to learn 31.10.2014 Vienna, Austria Althaus Christian;
 Epidemics4 - Fourth International Conference on Infectious Disease Dynamics Poster Determinants of viral persistence and clearance during HIV and HCV infections 19.11.2013 Amsterdam, Netherlands Althaus Christian;
 Swiss Meeting for Infectious Disease Dynamics (SMIDDY) 2013 Talk given at a conference Determinants of viral persistence and clearance during HIV and HCV infections 13.09.2013 Zürich, Switzerland Althaus Christian;
 20th International HIV Dynamics & Evolution Talk given at a conference Quantifying the turnover of transcriptional subclasses of HIV-1-infected cells 08.05.2013 Utrecht, Netherlands Althaus Christian;

#### Self-organised

Title Date Place
 Swiss Meeting for Infectious Disease Dynamics (SMIDDY) 2014 12.09.2014 Bern, Switzerland
 Swiss Meeting for Infectious Disease Dynamics (SMIDDY) 2013 13.09.2013 Zürich, Switzerland
 Swiss Meeting for Infectious Disease Dynamics (SMIDDY) 2012 30.08.2012 St. Gallen, Switzerland

### Communication with the public

Communication Title Media Place Year
 Media relations: print media, online media "Es würde genügen, die Übertragung von Ebola zu halbieren" Tages-Anzeiger German-speaking Switzerland 2014
 Media relations: print media, online media 20,000 cases or 100,000? How researchers predict Ebola’s spread. Washington Post International 2014
 Media relations: print media, online media Ebola - An der Schwelle zur Katastrophe Süddeutsche Zeitung International 2014
 Media relations: print media, online media Ebola: des semaines cruciales à venir La Presse International 2014
 Media relations: radio, television Ebola: Schweizer Forscher berechnen die Gefahr SRF 2 Kultur German-speaking Switzerland 2014
 Media relations: print media, online media Experimentelle Medikamente: Ebola-Patienten nicht als Versuchskaninchen missbrauchen NZZ German-speaking Switzerland 2014
 Media relations: radio, television Exponentieller Anstieg von Ebola in Liberia SRF 4 News German-speaking Switzerland 2014
 Media relations: radio, television Reproduktion von Ebola DRadio Wissen International 2014
 Media relations: radio, television Respekt, aber keine Angst: Schweizer Helfer im Ebola-Gebiet SRF 1 Puls German-speaking Switzerland 2014

### Associated projects

Number Title Start Funding scheme
 124952 Epidemiology and Mathematical Modelling for Infectious disease Control (EpideMMIC) 01.04.2009 ProDoc
 160320 Epidemiology and Mathematical Modelling for Infectious disease Control (EpideMMIC) 01.08.2015 Project funding (Div. I-III)
 118424 Integrating epidemiology and mathematical modelling to investigate the impact of interventions to control infectious diseases 01.05.2008 Project funding (Div. I-III)
 116862 Impact of HIV and antiretroviral therapy on Hepatitis C virus (HCV) evolution and on HCV-specific cellular immunity 01.06.2007 Project funding (special)
 148522 Swiss HIV Cohort Study (SHCS) 01.01.2014 Cohort Studies Large

### Abstract

Background:Human immunodeficiency virus (HIV) and hepatitis C virus (HCV) are potentially fatal RNA virus infections of public health importance. Both viruses can cause chronic persistence in infected individuals. Some patients, however, can clear HCV spontaneously during the acute phase of infection. For HIV, some individuals have been shown to control virus replication very effectively which results in a delayed disease progression. One key factor that has been found to determine the outcome of an infection is an individuals CD8+ T cell response which can suppress viral replication or mediate cytotoxic killing of infected cells. Due to their high mutation rate, both HIV and HCV can evade these immune responses through the occurrence of immune escape, i.e., mutant viral variants with altered epitopes that are not recognized by CD8+ T cells anymore. Together, there is a large body of evidence showing that CD8+ T cells induce a selection pressure on HIV and HCV. Mathematical modeling of virus dynamics has provided important insights into the interplay between viral replication and the immune response of the host. Nevertheless, it remains unclear when, how and to what extent the CD8+ T cells do interfere with HIV or HCV replication.Aims:The aims of this research project are: 1) to decipher characteristic aspects of the viral dynamics and evolution of HIV and HCV during the acute and chronic phase; 2) to use these insights in order to model the virus dynamics of HIV and HCV, specifically addressing the potential role of the CD8+ T cell response during the acute and chronic phase of both infections; 3) to investigate the epidemiological consequences of the observed within-host dynamics and evolution of HIV in response to the CD8+ T cell selection pressure with mathematical and computational models.Methods:Mathematical modeling of virus dynamics is a truly interdisciplinary research field and it is crucial to establish close collaborations with clinical experts and epidemiologists. To this end, I will use patient data provided from different institutions: the University Clinic of Infectious Diseases (University of Bern), the Division of Infectious Diseases and Hospital Epidemiology (University Hospital Zurich), the Swiss HIV Cohort Study (SHCS) and the Murdoch University in Perth (Australia).For the first aim of the project, I will analyze four different data sets from these institutions in order to study characteristic aspects of HIV and HCV during the acute and chronic phase of infection. Specifically for HIV, I will investigate the decay dynamics of the virus after combination antiretroviral therapy (cART) which provides information on the overall viral turnover and the lifespan of HIV-infected cells. For HCV, I will study the viral dynamics and evolution, in particular the occurrence of immune escape, which can provide information on the selection pressure that is induced on the virus population through the CD8+ T cell response.The insights from the data analysis are being used in the second aim of the project, where I will develop virus dynamics models based on ordinary differential equations that take into account the characteristic aspects of the viral dynamics and evolution of HIV and HCV. This will help to conceptually study the potential role that CD8+ T cells can play during the acute and chronic phase of an infection.For the third aim of the project, I will study the processes of viral adaptation within a host and between hosts with respect to immune escape in HIV by using mathematical and computational models. This will allow to critically investigate the interplay between the within-host evolution, the transmission of the virus and the immune system diversity of the host population.Rationale and significance:This research project will provide novel insights into the dynamics of HIV and HCV during the acute and chronic phase of infection. A better understanding of the characteristic properties of both viruses will help to better explain the outcome of an infection, e.g., why natural clearance only occurs in HCV but not in HIV and whether CD8+ T cells play a pivotal role in this process. Lastly, the novel insights into the population level adaption of HIV in respect to immune evasion from CD8+ T cell responses are of great interest to anticipate the ongoing epidemics, in particular in light of current efforts for vaccine design.
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