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Humoral immunity to HIV-1: Analysis of the function of antibody responses as correlate and surrogate marker of viremia control

English title Humoral immunity to HIV-1: Analysis of the function of antibody responses as correlate and surrogate marker of viremia control
Applicant Günthard Huldrych Fritz
Number 103748
Funding scheme Project funding
Research institution Abt. für Infektiologie und Spitalhygiene Universitätsspital Zürich
Institution of higher education University of Zurich - ZH
Main discipline Infectious Diseases
Start/End 01.04.2004 - 31.03.2007
Approved amount 260'000.00
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All Disciplines (2)

Discipline
Infectious Diseases
Clinical Immunology and Immunopathology

Keywords (6)

HIV-1; entry; CD4; coreceptor; chemokine; entry inhibitor

Lay Summary (English)

Lead
Lay summary
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.In general, this project tries to identify early virological features in HIV transmission. Further knowledge of such early events during HIV-infection are thought to play a key role in better understanding HIV-pathogenesis.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

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Associated projects

Number Title Start Funding scheme
65168 Analysis of the correlates of protection in structured intermittent therapy: An in vivo model of acute HIV infection? 01.10.2001 Project funding (special)
148522 Swiss HIV Cohort Study (SHCS) 01.01.2014 Cohort Studies Large
116035 Factors associated with viral control after primary HIV-1 infection and viral determinants associated with HIV-1 transmission 01.04.2007 Project funding (special)

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