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Günthard

Fakultäten » Medizinische Fakultät » Infektionskrankheiten und Spitalhygiene, Klinik für » Prof. Dr. Huldrych Günthard » Günthard

Completed research project

Title / Titel Factors associated with viral control after primary HIV-1 infection and viral determinants associated with HIV-1 transmission
PDF Abstract (PDF, 14 KB)
Summary / Zusammenfassung This translational research proposal addresses key questions of early pathogenesis in newly HIV-1 infected patients.

In the first aim, we will determine, whether early combination antiretroviral treatment initiated during primary HIV-1 infection (early-PHI-cART) can alter the course of disease. To date this remains undefined. We will test the hypothesis that early-PHI-cART can lower the viral setpoint. For this reason, we will compare viral setpoints of patients who stopped early-PHI-cART with viral setpoints of a control group of documented seroconverters of the Swiss HIV Cohort Study (SHCS), who have not received early-PHI-cART. Furthermore, we will determine whether early-PHI-cART delays CD4-count decline after therapy stop compared to the untreated seroconverter control group. These analyses do provide important answers to the highly clinically relevant question whether early-PHI-cART does delay disease progression and form the basis for aim two.

The objective of the second aim is to define virus determinants explaining viral setpoints reached in PHI patients who have stopped early-PHI-cART.
Here we aim at exploring viral determinants very early on after infection. First, we will systematically evaluate a variety of different cell-associated HIV nucleic acid species, by applying a panel of highly sensitive quantitative real-time RT-PCR assays, using patient matched primers. Specifically, we will test the predictive value of these parameters at baseline (before undergoing early cART) and before stopping cART. Second, we will study viral diversity at the time of PHI by clonal sequencing of the HIV-envelope C2V3C3 region. Specifically, we want to test the hypothesis that higher diversity is associated with higher viral setpoints. Moreover, detailed analysis of clonal sequences of transmitter-recipient pairs will potentially enable us to resolve the long-lasting issue, whether diversity present at PHI is due to early evolution in a given patient or rather to multiple infection events. Third, to test the phenotype of transmitted viruses with regard to intrinsic pathogenic properties, we will determine in vitro replication capacity (RC) of PHI patient-isolates and investigate whether RC correlates with viral setpoints.

In the third aim we will search for specific genetic signatures of newly transmitted HIV-1 strains. In a 1st step we will perform clonal sequencing of plasma HIV-RNA spanning the C2V3C3 env subregion in transmitters and recipients. In a 2nd step, full length gp160 env clones from plasma HIV-RNA of transmitter-recipient pairs will be analyzed. By applying a battery of phylogenetic, statistical and machine learning tools we will attempt to identify specific genetic signatures of viruses transmitted. The analyses proposed in aim three are unique in that larger numbers of transmitter- PHI pairs so far have not been identified.
Publications / Publikationen Trkola A, Kuster H, Leemann C, Ruprecht C, Joos B, Hirschel B, Weber R, Bonhoeffer S, Günthard HF, and the Swiss HIV cohort study. Cessation of antiretroviral treatment in chronic HIV-1 infection: Viral fitness is a determining factor of viral rebound and set point. Journal of Virology. 2003:77;13146-13155.

Fischer M, Joos B, Hirschel B, Bleiber G, Weber R, Günthard HF, for the Swiss HIV Cohort Study. Cellular viral rebound after cessation of potent antiretroviral therapy predicted by levels of multiply spliced HIV-1 RNA encoding nef. Journal of Infectious Diseases. 2004;190:1979-1988.

Trkola A, Kuster H, Rusert P, Joos B, Fischer M, Leemann C, Manrique A, Huber M, Rehr M, Oxenius A, Weber R, Stiegler G, Vcelar B, Katinger H, Aceto L, Günthard HF. Delay of HIV-1 rebound after cessation of antiretroviral therapy through passive transfer of human neutralizing antibodies. Nature Medicine. 2005:11:615-622.

Rusert P, Kuster H, Joos B, Misselwitz B, Gujer C, Leemann C, Fischer M, Stiegler G, Katinger H, Olson WC, Weber R, Aceto L, Günthard HF, Trkola A. Virus isolates during acute and chronic Human Immunodeficiency Virus Type 1 infection show distinct patterns of sensitivity to entry inhibitors. Journal of Virology. 2005;79:8454-8469.

Strain MC, Little SJ, Daar E, Havlir DV, Günthard HF, Lam RY, Daly OA, Nguyen J, Ignacio CC, Spina C, Richman DD, Wong JK. Effect of treatment, during primary infection, on establishment and clearance of cellular reservoirs of HIV-1. Journal of Infectious Diseases. 2005;191:1410-1418.

Joos B, Trkola A, Fischer M, Kuster H, Rusert P, Leemann C, Böni J, Oxenius A, Price DA, Phillips RE, Wong J, Weber R, Günthard HF, and the Swiss HIV Cohort Study. Low HIV-envelope diversity correlates with low in vitro replication capacity and predicts spontaneous control of plasma viremia after treatment interruptions. Journal of Virology. 2005;79:9026-9037.

Huber M, Fischer M, Misselwitz B, Manrique A, Kuster H, Niederöst B, Weber R, von Wyl V, Günthard HF and Trkola A. Complement lysis activity in autologous plasma is associated with lower viral loads during the acute phase of HIV-1 infection. PLOS Medicine 2006;3:2078-2093. (e441).

Keywords / Suchbegriffe HIV-1, viral setpoint, primary HIV infection, envelope, viremia control, antiretroviral treatment, transmission
Project leadership and contacts /
Projektleitung und Kontakte
Prof. Huldrych Günthard, MD (Project Leader) huldrych.guenthard@usz.ch
Funding source(s) /
Unterstützt durch
SNF (Personen- und Projektförderung)
 
In collaboration with /
In Zusammenarbeit mit
Swiss HIV Cohort Study

Prof. Alexandra Trkola, Division of Infectious Diseases, University Hospital Zurich, Zurich, Switzerland

PD Dr. M. Fischer, Division of Infectious Diseases, University Hospital Zurich, Zurich, Switzerland

Prof. A. Telenti, Institute of Medical Virology, CHUV, Lausanne

Prof. A. Oxenius, Institute of Microbiology, ETH Zürich
Switzerland
Prof. Dr. Joseph Wong, University of San Francisco, Veterans Affairs Medical Center, San Francisco

Dr. S. Pillay, University of San Francisco, Veterans Affairs Medical Center, San Francisco
United States
Duration of Project / Projektdauer Apr 2007 to Mar 2010