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DETEC
HIV/AIDS
Framework programme: 5
Project number:
QLK2-CT-1999-01215
EC contribution: € 1 778 342
Duration: 36 months
Type: RS
Starting date: 1 February 2001
Graphic element SIV/HIV Vaccines: Detecting Efficacy and Explaining Inefficacy
Keywords: Mucosal immunity; live attenuated vaccine; dendritic cell-based vaccine; immunopathology; viral load; complement; cytokine; lymph node; thymus; central nervous system

Summary:

The aim of this project has been to describe immune mechanisms that can impede replication of a wild type SIV during primary infection at the site of virus exposure and prevent the spread of infection in vaccinated rhesus macaques. Evaluation of early events that occur in situ in the tissue combined with in vitro studies will allow identification of important mechanisms of vaccine-induced immunity that could be missed in long-term experiments. Such knowledge would direct research activities toward the design of more efficient vaccines.

Problem:

The disease caused by HIV is an important public health problem, especially in the developing world. Therapeutic approaches that have been developed over the last several years have sharply reduced the pain, illness and mortality associated with HIV/AIDS in the industrialised countries.  However, it is now clear that the drugs used today are not sufficient to eradicate the virus. Life-long therapy is required to keep HIV replication at a very low level. Chemotherapy does not suppress virus replication in all patients due to the emergence of drug-resistant HIV variants. Therefore, antiretroviral therapy is likely to have a limited effect on containing AIDS. The development of an effective HIV-1 vaccine is one of the most urgent problems. Vaccines should prevent or dampen virus replication during primary infection. Mechanisms by which vaccination controls replication of the wild-type virus at the portal of entry, especially at mucosal surfaces, are not well understood. Therefore, the key issue is to study early events in lymphoid tissues as an index of how well the immune system initially contains the virus at the site of entry.

Aim:

The present project is designed to elucidate mechanisms that (i) are responsible for efficacy/inefficacy of a vaccine and (ii) assist the immune system in the generation of SIV-specific immune responses. To achieve this goal, macaques will be vaccinated either with live attenuated virus with a nef deletion or with dendritic cells carrying SIV genes as a result of infection with recombinant viral vector ex vivo prior to infusion and then challenged with a pathogenic SIV strain. The tonsillar model is used because it allows identification of the portal of virus entry with certainty, and to track the spread of infection within the various mircro-anatomic compartments of the portal of virus entry and to regional and remote lymph nodes.The virology, molecular histopathology, and immunology of monkeys before and after the challenge via the tonsils will be monitored. The dendritic cells will be targeted to try to increase immunity. By simultaneous quantification of infectious virus in blood and lymphoid cell suspensions, visualisation of cells replicating a virus or producing cytokines or chemokines in sections of lymphoid organs, and by measurement of humoral and cellular immunity as well as complement-mediated virolysis, the immune responses can be related to the extent of viral replication and spreading at critical sites in vivo. For the first time, mucosal associated and other lymphoid tissues will be monitored on a very broad basis in monkeys receiving various vaccine regimens.

Expected results:

  1. It is assumed that using the model presented here will make it possible to study the capacity of a host to limit the onset and spread of virus replication at critical lymphoid tissue sites.
  2. Studying the capacity of the host to limit virus replication will provide insight into immune mechanisms generated by vaccine approaches.
  3. The model used in the project provides valuable data on mucosal immunity.
  4. New information will be delivered on the relative potency of autologous DCs as adjuvants in vivo, relative to standard modes of SIV vaccine delivery.
  5. By targeting the immunising antigen(s) to appropriate antigen presenting cells, the project will help in the identification of rational targets and antigen delivery mechanisms.
  6. It is expected that a DC-based vaccine will generate marked antiviral immune responses that are beneficial for the course of the disease. 

Potential application:

Detailed information on how this project can assist the immune system in developing a specific immune response to SIV or HIV antigens is fundamental for future HIV vaccine strategies, and also for the prevention and treatment of HIV disease. In addition, such knowledge is also likely to provide concepts that will apply to other human pathogenic viruses and tumours.

Coordinator:

P. Racz and Klara Tenner-Racz
Bernhard-Nocht-Institute for Tropical Medicine
Bernhard-Nocht-Str. 74
20359 Hamburg
Germany
Tel: +49 40 42818 499
Fax: +49 40 42818 544
E-mail: racz@bni.uni-hamburg.de

Partners:

Principal
Scientific
Participants
Official Address Other Information
2Klaus UeberlaDepartment of Molecular and Medical Virology
Ruhr-University Bochum
Universitaetsstr. 150
DE-44780 Bochum
Germany
Tel: +49 234 3223189
Fax: +49 234 3214352
E-mail: klaus.ueberla@ruhr-uni-bochum.de
3Christiane Stahl-Hennig, V.M.D.Department of Virology and Immunology
German Primate Centre
Kellnerweg 4
DE -37077 Göttingen
Germany
Tel: +49 551 3851 154
Fax: +49 551 3851 184
E-mail: stahlh@dpz.gwdg.de
4Ralph Steinman
Henry G Kunkel
The Rockefeller University
Laboratory of Cellular Physiology and Immunology
1230 York Avenue
NY 10021-6399 New York
United States of America
Tel: +1 212 327 507 8106
Fax: +1 212 327 507 8875
Email: steinma@rockvax.rockefeller.edu
5M. P. Dierich and Heribert StoiberInstitute of Hygiene and Social Medicine
Fritz-Pregel-Straße 3
AT-6010 Innsbruck
Austria
Tel: +43 512 507 3400
Fax: +43 512 507 2870
E-mail: Hygiene@uibk.ac.at
Tel: +43 512 507 3405
Fax: +43 512 507 2870
E-mail: heribert.stoiber@uibk.ac.at
6Gudmundur GeorgssonInstitute for Experimental Pathology,
University of Iceland
Keldur v/Vesturlandsveg
IS -112 Reykjavik
Iceland
Tel: +354 567 4700
Fax: +354 567 3979
E-mail: ggeorgs@hi.is
7Carlo BaroniDipartimento di Medicina Sperimentale e Patologia
Policlinico Umberto I
Universita Degli Studi Di Roma ‘La Sapienza’
II Cattedra di Anatomia ed Istologia Pathologica
Sezione di Immunopatologia
Viale Regina Elena, 324;
IT-00161 Roma
Italy
Tel: +39 06 4468 606
Fax: +39 06 4940 896
E-mail: carlo.baroni@uniroma1.it
8Marco Baggiolini and Mariagrazia UguccioniInstitute for Research in Biomedicine
Via Vicenzo Vela 6
CH- 6500 Bellinzona
Switzerland
Tel: +41 91 8200 300
Fax: +41 91 8200 302
E-mail: baggiolini@unisi.ch
Email: mariagrazia.uguccioni@irb.unisi.ch
9Ralf IgnatiusInstitute for Medical Microbiology
Free University Berlin
Hindenburgdamm 27;
DE-12203 Berlin
Germany
Tel: +49 30 8445 3620
Fax: +49 30 8445 3830
E-mail: ralf.ignatius@ukbf.fu-berlin.de

 
 
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