T-cell dynamics in chronic viral infection

Abstract

In this thesis we investigate how chronic HIV and CMV infections impact on the human T-cell compartment. How untreated HIV infection affects the turnover of human CD4+ and CD8+ T cells is described in chapter 2. In this chapter, T-cell turnover in untreated HIV infected individuals is compared to that in healthy individuals. To investigate whether certain HIV-induced alterations in the human T-cell compartment are reversible during therapy, we analyze T-cell turnover during cART with an in depth investigation of the role of the HIV entry inhibitor Maraviroc in immunological non-responders, a specific group of HIV infected individuals in which viral replication is controlled but immune recovery is slow, in chapter 3. Maraviroc and placebo treated individuals within the same clinical trial were compared in terms of T-cell turnover and life span. Functional and phenotypical changes in T cells during cART intensification with Maraviroc are characterized in chapter 4. In this placebo controlled clinical trial, Maraviroc treated individuals were followed longitudinally for 48 weeks, from the start of Maraviroc treatment intensification. Chapter 5 explores whether CD8+ T-cell numbers, which are expanded in untreated HIV infected individuals normalize during cART. This is investigated cross-sectionally after at least 5 years of successful cART. Chapter 6 covers the changes that chronic CMV infection induces in the CD8+ T-cell compartment. In a large cohort of children and adults, phenotypical characteristics of T cells from CMV seropositive and CMV seronegative individuals were compared. Chapter 7 focuses on the measurement of TCR diversity since this is an important tool to analyze the functionality of the human T-cell compartment. We optimized the AmpliCot method for the measurement of TCR diversity with mathematical modeling in this chapter.