Project

Discipline

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

Lead
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

Active participation

Self-organised

Communication	Title	Media	Place	Year

Number	Title	Start	Funding scheme

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.