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Determinants of the Development and Evolution of HIV-1 Drug Resistance

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Determinants of the Development and Evolution of HIV-1 Drug Resistance Determinants of the Development and Evolution of HIV-1 Drug Resistance Axel Fun Determinants of the Development and Evolution of HIV-1 Drug Resistance PhD Thesis, University of Utrecht, the Netherlands Print: Gildeprint drukkerijen, Enschede, the Netherlands ISBN: 978-90-393-5722-4 Coverdesign: Axel Fun and Carlijn van Merode Cover: Flowing waters from nearby hot springs spill across the surface to sculpt magnificent travertine limestone terraces. Mammoth Terraces at Mammoth Hot Springs, Yellowstone National Park, USA. Printing of this thesis was financially supported by the Infection and Immunity Center Utrecht, Merck Sharp & Dohme BV, The Netherlands, Gilead Sciences Netherlands BV and ViiV Healthcare BV. Determinants of the Development and Evolution of HIV-1 Drug Resistance Determinanten van de Ontwikkeling en Evolutie van HIV-1 Medicijn Resistentie (met een samenvatting in het Nederlands) Proefschrift ter verkrijging van de graad van doctor aan de Universiteit Utrecht op gezag van de rector magnificus, prof. dr. G.J. van der Zwaan, ingevolge het besluit van het college voor promoties in het openbaar te verdedigen op donderdag 19 januari 2012 des middags te 2.30 uur door Axel Fun geboren op 7 juni 1981 te Stad Delden Promotor: Prof. dr. E.J.H.J. Wiertz Co-promotoren: Dr. M. Nijhuis Dr. A.M.J. Wensing “Satisfaction of one’s curiosity is one of the greatest sources of happiness in life.” -Linus Pauling- Voor mijn ouders Voor Carlijn Commissie: Prof. dr. R..J. de Boer Prof. dr. M..J.M. Bonten Prof. dr. A.I.M. Hoepelman Prof. dr. F. Miedema Prof. dr. L.P.R. Vandekerckhove Paraninmfen: Evelien Oostdijk Marieke de Regt Contents Chapter 1 General Introduction 9 Partly derived from review articles: Human Immunodeficiency Virus Protease and Gag: Partners in Resistance Submitted for publication Current and Future Integrase Inhibitors: a Systematic Review of literature and Clinical Indications Submitted for publication Chapter 2 In Vitro Selection of High Level Darunavir Resistance in 37 the Absence of Darunavir Resistance Mutations in the Viral Protease In preparation Chapter 3 High Prevalence of Bevirimat Resistance Mutations in 51 Protease Inhibitor-Resistant HIV Isolates AIDS 2010; 24(5):669-673 Chapter 4 HIV-1 Protease Inhibitor Mutations Affect the Development 63 of HIV-1 Resistance to the Maturation Inhibitor Bevirimat Retrovirology 2011; 8:70 Chapter 5 Mutation Q95K Enhances N155H-Mediated Integrase 87 Inhibitor Resistance and Improves Viral Replication Capacity Journal of Antimicrobial Chemotherapy 2010; 65(10):2300-2304 Chapter 6 Impact of the Genetic Background and Population Size 97 on the Evolution of Raltegravir Resistance In preparation Chapter 7 General Discussion 119 Partly derived from review article: Human Immunodeficiency Virus Protease and Gag: Partners in Resistance Submitted for publication Nederlandse samenvatting 137 Publication list 145 Dankwoord/Acknowledgements 147 Curriculum Vitae 151 Chapter 1 General Introduction Partly derived from review articles: Human Immunodeficiency Virus Protease and Gag: Partners in Resistance Axel Fun1, Annemarie MJ Wensing1, Jens Verheyen2 and Monique Nijhuis1 1Department of Virology, Medical Microbiology, University Medical Center Utrecht, The Netherlands; 2Department of Virology, University of Cologne, Cologne, Germany Submitted for publication Current and Future Integrase Inhibitors: a Systematic Review of Literature and Clinical Indications Peter Messiaen1, Annemarie MJ Wensing2, Monique Nijhuis2, Axel Fun2 and Linos Vandekerckhove1 1AIDS Reference Laboratory, Ghent University, Ghent, Belgium; 2Department of Virology, Medical Microbiology, University Medical Center Utrecht, The Netherlands Submitted for publication 10 Chapter 1 The human immunodeficiency virus (HIV) epidemic is still a global health problem with an estimated 33.3 million people infected and 2.6 million newly infected worldwide in 2009[1]. The vast majority is infected with human immunodeficiency virus type 1 (HIV-1). Intensive prevention campaigns and expanding access to treatment resulted in a 19% decline of new infections compared to 1999, the year in which it is thought the epidemic peaked. Despite the global decline of new infections, the incidence in certain risk groups is still rising. For instance, both in the United States and in the Netherlands, the incidence of new HIV diagnosis in young MSM has been steadily rising in recent years[2, 3]. Due to the expanded access to treatment programs, more than 5 million people receive antiretroviral therapy in low- and middle-income countries, which led to a drop in acquired immunodeficiency syndrome (AIDS)-related deaths[1], although early mortality after the initiation of treatment is still a major concern. In the Western countries, the introduction of highly active antiretroviral therapy (HAART) in 1995 resulted in a spectacular improvement of virological suppression rates which led to a dramatic reduction of HIV-1 related morbidity and mortality[4]. Despite these achievements, drug resistance challenges the success of antiretroviral therapy, especially in low and middle income countries where resources and therapeutic options are not as extensively available as in the industrialized countries. With the continually increasing number of people receiving antiretroviral therapy, the incidence of resistance and associated complications are likely to increase in the future. In vivo evolution of HIV The diversity and size of the HIV population within a host is a direct result of a combination of viral and host factors. They include viral replication capacity, the mutation rate of the virus, host cell tropism, the rapid turn-over of viral particles and infected cells, the genetic background of the host (e.g. HLA-type, CCR5Δ32), immune control and target cell availability. HIV has a very high mutation rate which is a feature that is shared by all RNA viruses. The underlying biochemical principal of this high mutation rate is the low fidelity of viral RNA polymerases and reverse transcriptases because these enzymes lack 3’→5’ exonuclease activity, which is a proof-reading mechanism that amends incorrect base-pair insertions. Although the in vivo error rate of HIV-1 reverse transcriptase appears to be lower than predicted from in vitro studies[5-8], the error-rate is still more than a 100,000 times higher than during in vivo DNA transcription in eukaryotic cells, which is approximately one per 10 billion (10-10) basepairs per replication cycle[9, 10]. The estimated in vivo mutation rate of HIV-1 is 3.4x10-5 per basepair per replication cycle[8], which, when multiplied with the size of the HIV-1 genome of about 10 kb, translates to approximately one third of all newly General Introduction 11 generated virus particles containing a change in the viral genome. The high turnover rate of HIV is characterized by rapid clearance of virions and productively infected cells, especially early in infection[11-14]. During acute infection, viral doubling Chapter 1 Chapter time (t2) is estimated to be 10-16 hours[14, 15], which combined with the abundance of permissive target cells can result in extremely high levels of viremia (up to 44 million copies per ml of plasma have been measured)[14]. The doubling time during acute infection is about 3-4 times faster than after treatment interruption during chronic infection (t2 = 1.4- 1.6 days)[16, 17]. The half-life of virions is estimated to be 6-8 hours and that of productively infected cells around 1.5 days. From these data different basic reproductive numbers (R0) have been calculated. Where Little et al[14] calculated that each productively infected cell produces an average of 19 new productively infected cells, Ribeiro et al[15] estimated an R0 of 8.8. The combined high turnover rate and error-prone replication cycle is thought to result in a large and diverse HIV population. However, there is ongoing debate about the exact size and especially the diversity of the population. The concept of population size is critical for understanding the with-in host evolution of HIV-1. The population size ultimately determines if development of HIV-1 drug resistance is largely driven by stochastic or deterministic forces. Considering the large census population within a patient of typically 107-108 HIV-1 infected cells[18], deterministic evolution might seem the major driving force. However, large differences between infected individuals in virological parameters such as viral load set point and rates of emergence and patterns of drug resistance, suggested a more stochastic evolution[19, 20]. In fact, the relevant (effective) population size is always smaller than the census population size. Every productively infected cell produces >1 progeny, therefore all infected cells of a certain generation can not be infected by all productively infected cells of the previous generation, but only by a limited number of infected cells from that generation[21]. Therefore, not every infected cell contributes to the next generation and only the ones that do also contribute to the within host evolution. The number of viral variants that contribute to within host evolution is referred to as the effective population N( e). The mathematical definition of Ne is the size of an idealized population that has the same population genetic properties as the natural population[22] and is an important parameter in models used to study the effect of deterministic and stochastic forces on HIV-1 evolution. To date, many different models have been proposed and large discrepancies exist in the estimates of 2 6 Ne, ranging from 10 to 10 [20-30]. Interestingly, the different estimates span the inverse mutation rate of HIV-1 replication (~10-5), leaving the question whether deterministic or stochastic forces dominate HIV evolution unanswered. 12 Chapter 1 Antiretroviral therapy and drug resistance Zidovudine (AZT) marked the initiation of antiretroviral therapy in 1987, but already soon after its introduction drug resistance was recognized as a serious problem. The subsequent development of other nucleoside reverse-transcriptase inhibitors (NRTIs) revealed that monotherapy would not be able to combat HIV infection very effectively; resistance emerged readily and rapidly.
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