HIV-X Deciphering host-virus interactions to cure HIV
In order to develop strategies with which the HIV reservoir can be eliminated, we need first to understand how HIV manages to establish and maintain the latent reservoir. To achieve this ambitious goal, a nationwide and interdisciplinary project, called HIV-X has been started in February 2015. Based on the Swiss HIV Cohort Study, which was initiated in 1988 and covers more than half of all registered HIV-infected individuals in Switzerland, we will study a group of approximately 1,600 HIV-1 infected individuals longitudinally who have been treated successfully with antiretroviral therapy. Our group is measuring the decay rate of the latent reservoir as well as the viral genome sequencing in these individuals using the most modern methods. Besides us, the following research groups are participating: Prof. Huldrych Günthard (UZH/USZ, principal investigator) Prof. Niko Beerenwinkel (ETHZ, SIB), Dr. Jasmina Bogojeska (IBM), Prof. Sebastian Bonhoeffer (ETHZ), Prof. Jacques Fellay (EPFL), Prof. Roger Kouyos (UZH/USZ), Prof. Volker Roth (UniBas).
HIV-1 integration sites and their impact on HIV-1 pathogenesis
Anne Inderbitzin (PhD student)
Although an HIV-1 infection can be effectively treated, its cure is impeded by the persistence of the latent HIV-1 reservoir, which is invisible to the host immune surveillance and unsusceptible to antiretroviral therapy. Latent HIV-1 proviruses are transcriptionally silent. This project involves the examination of HIV-1 integration sites in search of factors that govern the transcriptional activity of HIV-1 proviruses.
Molecular epidemiology and prevalence of drug resistance-associated mutations in drug-naive and newly diagnosed HIV-1 infected patients in Cameroon
Herbert Afegenwi Mbunkah (PhD student)
Antiretroviral therapy has turned a deadly infection with HIV-1 into a chronic life-long disease. However, this can be compromised by the development of drug resistance. In Cameroon, not all options for combination ART are available and so, it is even more important to watch out for the emergence of drug-resistant HIV-1 that leads to virological failure in treated patients. This may subsequently lead to transmission of drug-resistant HIV-1 to the uninfected, diminishing future ART options for these individuals.
We are working on determining the prevalence and recent trends in the emergence of drug resistance-associated mutations in untreated HIV patients from Cameroon, using a Next-Generation Sequencing assay suitable for all HIV-1 subtypes. Data generated will better inform optimal antiretroviral therapy delivery in Cameroon.
Targeting the HIV-1 latent reservoir with CRISPR/Cas9
Sarah Klinnert (PhD student)
The main hurdle towards a cure of HIV-1 is the presence of the HIV-1 latent reservoir, which is defined as transcriptionally inactive, integrated HIV-1 proviruses that persist life-long in the human body, hidden from the immune system.
We aim to utilize the state-of-the-art CRISPR/Cas9 gene editing technology in two different strategies to uncover and eliminate these latently HIV-1 infected cells. In the first approach, we aim to activate the latent proviruses by using a CRISPR activation system. Thereby, we want to favor subsequent elimination of formerly latently infected cells and also of the reactivated virus by cytopathic viral effects, immune surveillance mechanisms, and antiretroviral therapy. Second, we seek to target different regions of HIV-1 to excise crucial viral genes and/or to introduce mutations to render the provirus replication defective. Both approaches will be combined with a retargeted adenoviral delivery system, which allows specific delivery into the major part of the latent reservoir, namely CD4+ resting memory T-cells.
This project is a collaborative effort together with Prof. Alexandra Trkola’s and Prof. Andreas Plückthun’s groups (UZH).
Collaborations and support
All our projects are carried out in close collaboration with the research groups of Prof. Huldrych Günthard and Prof. Roger Kouyos here at our Division of Infectious Diseases. Together, we are a University Hospital based research team interacting with a variety of collaborators to study the pathogenesis of HIV-1 from a broad range of angles. This is possible due to our translational approach, i.e., we are studying HIV-1 pathogenesis in HIV-1 infected individuals who are longitudinally followed up in our outpatient clinic and the Swiss HIV Cohort Study over many years.
Our projects are supported by the Swiss National Science Foundation, SystemsX.ch - the Swiss Initiative in Systems Biology, the Swiss HIV Cohort Study, National Institutes of Health (NHI), ESTHER Switzerland, the Hartmann Müller Foundation, unrestricted grant by Gilead Sciences and a Schweizerische Bundes-Exzellenz-Stipendium to Herbert Afegenwi Mbunkah.