Objective
A. BACKGROUND
Small ruminant lentiviruses are a sub-family of retroviruses and cause important diseases in sheep and goats; maedi-visna and caprine arthritis-encephalitis. These viruses share a number of features with the human immunodeficiency viruses HIV-1 and 2, including a long preclinical period (months to years) and the progressive and fatal nature of the illness. Maedi-visna and caprine arthritis-encephalitis viruses (MVV and CAEV respectively) cause a multi-system disease of sheep and goats; they are a significant problem in veterinary medicine, causing important losses in sheep and goat industries and create increasing threats for commercial flocks in most of the European countries.
The French proposal for a new COST Action on Lentiviruses of sheep and goats is the convergence of three ideas:
- first, an informal group already exists; this group set up two meetings about small ruminant lentiviruses (the last meeting was held in La Londe-les-Maures, France, October 1994); this new COST Action will better structure this group and will allow this group to be opened to other European laboratories involved in the study of lentiviral infections;
- second, lentiviruses interest different disciplines, and this COST Action will be an interesting place to put together teams from different horizons: veterinary medicine, human medicine, fundamental biology, etc.
- third, the complexity and difficulties to comprehend the biology of lentiviruses and their control require the development of a global strategy and the strengthening of the coordination between teams involved in this field at European level.
The proposal has the following scientific objectives: to analyse the viral factors involved in the virulence and pathogenesis of ovine and caprine lentiviruses in their natural hosts; to study the genetic variability of these lentiviruses in natural infections; to use this information for epidemiological purposes and development of strategies to control disease caused by lentivirus infections (improvement of diagnostic tools, vaccination).
The proposed Action is innovative, interdisciplinary and is of high importance for the European continent. Its benefits will be easily shared by all European countries: standardization of diagnostic procedures and development of new strategies will help to control better the lentiviral diseases of sheep and goats, and to avoid spread of diseases within the international trade in animals.
B. OBJECTIVES AND BENEFITS
1. Grounds for desirability of carrying out the proposed research Action in the framework of COST cooperation
Lentiviral infections of small ruminants cause losses; culling of animals with clinical signs ("big knees", "hard udder", pneumonia etc.), culling of seropositive animals, decrease of milk production, hindrance to selling animals of high genetic value. All European countries face great economic problems related to MVV and CAEV infections;
Maedi-visna and caprine arthritis-encephalitis are notified in the OIE list B diseases; OIE needs clear rules and standardized methods to promote the free trade in live animals between European countries and within the world. Two of three OIE reference laboratories with regard to Maedi-visna and CAE are located in Europe (France and United Kingdom): it is very important that standardized and new methods for diagnosis should be developed and validated by European countries. The COST network must reinforce the European position to validate standard methods;
due to the high prevalence of lentiviral infections; it is important to develop at the European level an important effort for developing diagnostic tools; this development must be coordinated in countries interested in their application for disease control in order to achieve standardization of procedures: this represents an important task and challenge for Europe. Due to the high complexity of these infectious agents, a collaborative effort between laboratories with different specialities and different interests will be essential.
The support by an international programme such as COST will give a new impetus in this active area. To achieve the goals of this Action, it is important to allow laboratories from different horizons to be gathered in this project and must lead to an exchange between field studies and molecular studies on MV and CAE viruses.
the similarities of MV and CAE viruses with human immunodeficiency viruses are another important reason to carry out research on small ruminant lentiviruses: this new Action will attract groups involved in the HIV field and this involvement will be of benefit for all scientists working on lentiviruses.
2. General objectives
The main objectives of the proposal are:
(1) to determine the viral factors involved in the virulence and the pathogenesis of ovine and caprine lentiviruses in their natural hosts, and the consequences to improve our knowledge about HIV;
(2) to study the genetic variability of ovine and caprine lentiviruses in natural and experimental infections, and the consequences for diagnosis of these infections;
(3) to develop new tools for improving diagnosis of MVV and CAEV infections in sheep and goats;
(4) to develop strategies for vaccination against MVV and CAEV infections.
3. Secondary objectives
The new COST Action has also other objectives which will be realized in the progress of the studies;
(1) to standardize techniques already used or newly developed for diagnosis; these techniques include serology by agar gel immunodiffusion or by ELISA; this point is very important in regard to the trade in animals within European countries or with other countries. This point concerns particularly the Office International des Epizooties (OIE) which must develop standardized techniques for qualification of flocks or animals.
(2) to promote the MVV and CAEV infections as models for HIV infection, particularly concerning the vaccination and the role of macrophage in lentivirus pathobiology, and also as a model for testing candidate anti-HIV drugs. There are a number of important similarities between the ovine/caprine and human lentiviral infections, but the major difference in the expression of lentiviral diseases between the two groups is the lack of immunosuppression in infected goats and sheep, probably related to the minimal infection of lymphocytes in the ruminants. This difference provides an opportunity to examine the role of the macrophage in the pathogenesis of lentivirus-induced lesions without the confounding factors of lymphocyte infection and the resultant immunosuppression. The study of immune mechanisms involved in MVV and CAEV infections will be particularly useful for this objective (comparative pathology), and to determine protective factors in asymptomatic animals.
4. Benefits of the proposed research Action
The proposed project is firstly justified at the Community level for scientific reasons. Indeed, in face of the complexity of the lentiviruses life cycle in terms of variability and in terms of diseases induced in two animals species (sheep and goats) it is urgent to strengthen and coordinate the competence of the European laboratories working in the field.
With the present proposed collaborative network, the European Community has the possibility to meet the challenge:
(1) to improve present diagnostic techniques or to develop new diagnostic tools;
(2) to develop a protective vaccine against lentiviruses infections, which could be an extraordinary example for the AIDS vaccine field;
(3) to define the consequences of virus variability on diagnosis or vaccination.
The compilation of nucleotide sequence data from viral genes of lentiviruses from all the European countries will be of benefit to control the spread of these viruses in Europe and determine the number of types and subtypes which may exist.
The control for the presence of lentiviruses in imported animals from other continents, such as North or South America, Australia, South Africa and New Zealand by PCR techniques will be then useful to avoid the entry of new types or subtypes of viruses.
C. SCIENTIFIC PROGRAMME
The proposed research action has as its main goal that of improving our fundamental knowledge about the molecular mechanisms in lentiviral diseases; this knowledge is not only essentially to understand pathogenesis of MVV and CAEV viruses and their consequences in infected animals but also to develop new methods for controlling the diseases, as the result of the high incidence of MVV and CAEV infections in European countries. This goal will only be achieved with the help of a close collaboration between teams involved in this field.
The Action can be grouped into 4 different topics with multiple links, corresponding to four working groups:
Working group 1: Role of structural and accessory genes in MV and CAE viruses and Understanding of the pathogenesis of MVV and CAE viruses: the studies already undertaken about this topic must be continued to maintain the advance of European groups in this area; this group will carry on studies on deleted viruses and the pathogenicity in experimentally-infected animals (transgenic animals) [Vellutini et al, 1994], immunization of sheep or goats with DNA, etc.), in order to clarify the role of deleted genes in MVV and CAEV infections. These will gain new insights into the pathogenesis of lentiviral infections.
Working group 2: Molecular epidemiology and variability of MV and CAE viruses: this aims to collect various strains in different countries and to analyse their variability by different techniques of molecular epidemiology (PCR and sequencing); this working group needs a strong cooperation between researchers in order to compare their results and to exchange their strains, and to establish a complete map of distribution of MV and CAE viruses. This group will coordinate epidemiological studies and modelization of infection in contaminated flocks;
Working group 3: Improvement of diagnostic tools and development of new diagnostic techniques: this includes cloning and expression of gene coding for immunogenic factors; production of antigens by recombinant DNA methodology; analysis of the immunogenic kinetics of such antigens during experimental and natural infection; production of serological analysis procedures using such antigens; production of specific monoclonal antibodies; developments of DNA based methodology for the detection of MV and CAE viruses in milk, blood, and organs. Experimentally infected animals will provide specimens in order to standardize isolation methods, DNA or antigen based detection methods developed in the different laboratories for diagnostic methods or for basic research. The production of standard sera used in serological methods will be an important and necessary part of this topic;
Working group 4: Feasibility of vaccination against lentiviruses:
- by live attenuated viruses deleted in accessory genes; obtention of deleted mutants; studies in vivo of the properties of mutants; verification of the attenuated phenotype of these mutants in the natural host (sheep and goats); protective role by using different routes of inoculation and different systems of delivery (conventional inoculation of attenuated viruses or genetic immunization);
- by using eucaryotic vectors expressing viral proteins;
- by using recombinant Salmonella abortusovis strain Rv6 carrying lentiviral genes, the same approach used for attenuated viruses can be applied to establish the protective role of recombinant bacteria.
D. ORGANIZATION AND TIMETABLE
1. Organization and timetable
The organization and coordination of the Action will be carried out by the Management Committee (MC). The MC will be set up during a meeting in Brussels organized by the COST Secretariat; during this meeting, a president and a vice-president will be designated. Thereafter, the MC will have the responsibility of organizing the first seminar with all the participants in the COST Action.
Each working group will have a coordinator (and a substitute) to follow the progress of tasks in the group, to promote the organization of mid-term workshops and to promote the mobility of researchers and technicians between laboratories involved in this working group. This last point will be one of the most important in order to make this COST Action successful.
The following activities are planned:
- one COST meeting during the first year;
- one subgroup meeting/year (end of the 2nd year and 4th year);
- a mid-term meeting at the end of the 3rd year;
- visits in collaborative institutes;
- a final meeting at the end of the COST Action (5th year).
After the mid-term workshops, it could be proposed to merge working groups 1 and 4 together and working groups 2 and 3 together until the end of the Action. The Action will be ended by a final meeting gathering all the researchers involved in the Action; this final meeting should be structured in a manner to edit in a book all the results and conclusions of the COST Action.
2. Duration of the proposed research Action
This new research Action is proposed for a duration of 5 years.
E. ECONOMIC DIMENSION
1. Financial efforts supported by countries in this field.
The following COST countries have actively participated in the preparation of the action or otherwise indicated their interest:
THE NETHERLANDS, UNITED KINGDOM, SPAIN, SWITZERLAND, ICELAND, FINLAND and FRANCE.
In each participating country, 3 to 4 persons are expected to devote their work to projects which concern this proposed COST Action. For example, for 7 countries which are estimated to participate in the main tasks, 24 persons in total per year are estimated, amounting to 5 years x 24 persons = 120 person-years which will form the basic work power in this Action.
The total economic impact includes:
Scientists
10 persons x ECU 60 000
ECU 600 000
Technicians
8 persons x ECU 40 000
ECU 320 000
PhD students
6 persons x ECU 25 000
ECU 150 000
TOTAL personnel/year
ECU 1 070 000
Total personnel
x 5 years
ECU 5 350 000
Total investment
x 5 years
ECU 800 000
Total running costs
x 5 years
ECU 1 000 000
Coordination costs (COST)
x 5 years
ECU 350 000
TOTAL
ECU 7 500 000
So on this basis, the overall cost of the activities to be carried out under the Action has been estimated, at 1997 prices, at roughly ECU 7,5 million.
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Coordinator
France
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