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See detailA life-attenuated BLV deletant as a candidate vaccine to inhibit viral transmission in bovine herds
Rodriguez, Sabrina ULg; Gutiérrez, G.; Florins, A. et al

Scientific conference (2011, June 06)

A life-attenuated BLV deletant as a candidate vaccine to inhibit viral transmission in bovine herds Sabrina M. Rodríguez1*†, Gerónimo Gutiérrez2*, Arnaud Florins3, Lucas Vagnoni2, Irene Alvarez2, Nicolas ... [more ▼]

A life-attenuated BLV deletant as a candidate vaccine to inhibit viral transmission in bovine herds Sabrina M. Rodríguez1*†, Gerónimo Gutiérrez2*, Arnaud Florins3, Lucas Vagnoni2, Irene Alvarez2, Nicolas Gillet1, Karina Trono2‡, Luc Willems1,3‡ *‡S.M. Rodríguez / G. Gutiérrez and K.Trono / L. Willems contributed equally to this work. 1 Molecular and Cellular Epigenetics, Interdisciplinary Cluster for Applied Genoproteomics (GIGA), University of Liège (ULg), Liège (4100), Belgium. 2 Instituto de Virología, CICVyA, Instituto Nacional de Tecnología Agropecuaria, (1712), Castelar, Argentina. 3 Molecular and Cellular Biology, Gembloux Agro-Bio Tech, University of Liège (ULg), Gembloux (5030), Belgium †E-mail: sabrina.rodriguez@ulg.ac.be Bovine Leukemia Virus (BLV) is a major sanitary concern in many countries where the virus is widely disseminated among dairy herds with obvious economic impact. Different control strategies have been implemented worldwide to control BLV infection or eradicate the disease with diverse success. Eradication by culling is not economically sustainable in highly infected regions such as Argentina, US or Japan. Segregation of BLV-infected cattle is expensive due to duplication of facilities. Finally, several candidate vaccines based on recombinant viral proteins were unsuccessful to protect from challenge. Therefore, here we propose a novel strategy aimed to decrease seroprevalence based on the employ of a life-attenuated BLV provirus as a candidate vaccine. The rationale behind this strategy is the deletion of genes required to induce pathogenesis leaving those involved in infectivity, resulting in an attenuated deletant with impaired transmissibility. Preliminary experiments showed that the deletant provirus is infectious and elicits an efficient immune response in sheep (n=3) and in the natural host, bovines (n=9). Lack of spread to sentinels further supports the safety of the vaccine. Based on these promissory results, an ongoing validation program is being performed to evaluate the capacity of the candidate vaccine to protect from wild-type BLV infection in herd conditions (n=105). Infection will be routinely monitored and proviral loads will be determined. The efficiency of the immune response will be evaluated by titration of specific antibodies, cytotoxic lysis efficiency and cytokine profile. Viral expression ex vivo and provirus clonality will be also evaluated. This data will be instrumental for understanding the basic mechanisms undergoing during BLV infection and for elaborating a novel vaccine. We do believe this practical and cost-effective vaccination strategy is the sole economically viable in countries with high prevalence. [less ▲]

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See detailHTLV-1 clonality during chronic infection and BLV clonality during primary infection
Gillet, N.; Hlela, C.; Verdonck, T. et al

in AIDS Research and Human Retroviruses (2011, June 06), 8(1), 185

HTLV-1 clonality during chronic infection and BLV clonality during primary infection Nicolas A Gillet1,2*, Carol Hlela1, Tine Verdonck3, Eduardo Gotuzzo3, Daniel Clark3, Sabrina Rodriguez2, Nirav Malani4 ... [more ▼]

HTLV-1 clonality during chronic infection and BLV clonality during primary infection Nicolas A Gillet1,2*, Carol Hlela1, Tine Verdonck3, Eduardo Gotuzzo3, Daniel Clark3, Sabrina Rodriguez2, Nirav Malani4, Anat Melamed1, Niall Gormley5, Richard Carter5, David Bentley5, Charles Berry6, Frederic D Bushman4, Graham P Taylor7, Luc Willems2, Charles R M Bangham1 1Department of Immunology, Wright-Fleming Institute, Imperial College London, London, W2 1PG, UK. 2Molecular and Cellular Epigenetics, Interdisciplinary Cluster for Applied Genoproteomics (GIGA) of University of Liège (ULg), Liège, 4000, Belgium. 3Instituto de Medicina Tropical Alexander von Humboldt, Universidad Peruana Cayetano Heredia, Lima, Peru. 4Department of Microbiology, University of Pennsylvania School of Medicine, Pennsylvania, Philadelphia, PA, 19104, USA. 5Illumina, Chesterford Research Park, Essex, Little Chesterford, CB10 1XL, UK. 6University of California, California, La Jolla San Diego, CA, 92093-0901, USA. 7Department of Genitourinary Medicine and Communicable Diseases, Wright-Fleming Institute, Imperial College London, London, W2 1PG, UK. HTLV-1 persists by driving clonal proliferation of infected T-lymphocytes. A high proviral load predisposes to the inflammatory and malignant diseases associated with HTLV-1. Yet the reasons for the remarkable variation within and between individuals in the abundance of HTLV-1-infected clones remain unknown. We demonstrate that negative selection dominates during chronic infection, favouring establishment of proviruses integrated in transcriptionally silenced DNA: this selection is significantly stronger in asymptomatic carriers. We postulated that this selection occurred mainly during the primary infection. We are testing this hypothesis in an animal model by studying the BLV clonality during the primary infection in cows. By measuring the proviral load, the anti-BLV immune response and the BLV clonality we aim to quantify the impact of the immune response on the rate of infectious spread and on the selection of proviruses inserted in a particular genomic environment. Co-infection with Strongyloides stercoralis or Staphylococcus appears to be another risk factor for the development of HTLV-1 associated diseases. We observed that HTLV-1 clonality is altered by co-infection with these pathogens with an increase of both the number and the abundance of the infected T-cell clones. The genomic characteristics of the proviral integration sites in the most abundant clones differ significantly between co-infected individuals and those with HTLV-1 alone, implying the existence of different selection forces in co-infected patients. The rate of appearance of new clones in patients co-infected with Strongyloides stercoralis is higher than in patients with HTLV-1 alone. By comparing skin lesions and blood samples from patients with Infective Dermatitis associated with HTLV-1 (IDH), we observed a significant proportion of distinct infected clones between the two compartments. The skin lesions seem to be a site for HTLV-1 infectious spread. [less ▲]

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See detailA life-attenuated BLV deletant as a candidate vaccine to inhibit viral transmission in bovine herds
Gutiérrez, G.; Rodriguez, Sabrina ULg; Florins, A. et al

in AIDS Research and Human Retroviruses (2011, June 05), 8(1), 12

A life-attenuated BLV deletant as a candidate vaccine to inhibit viral transmission in bovine herds Gerónimo Gutiérrez2*, Sabrina M. Rodríguez1*†, Arnaud Florins3, Lucas Vagnoni2, Irene Alvarez2, Nicolas ... [more ▼]

A life-attenuated BLV deletant as a candidate vaccine to inhibit viral transmission in bovine herds Gerónimo Gutiérrez2*, Sabrina M. Rodríguez1*†, Arnaud Florins3, Lucas Vagnoni2, Irene Alvarez2, Nicolas Gillet3, Karina Trono2‡, Luc Willems1,3‡ *‡S.M. Rodríguez / G. Gutiérrez and K.Trono / L. Willems contributed equally to this work. 1 Molecular and Cellular Epigenetics, Interdisciplinary Cluster for Applied Genoproteomics (GIGA), University of Liège (ULg), Liège (4100), Belgium. 2 Instituto de Virología, CICVyA, Instituto Nacional de Tecnología Agropecuaria, (1712), Castelar, Argentina. 3 Molecular and Cellular Biology, Gembloux Agro-Bio Tech, University of Liège (ULg), Gembloux (5030), Belgium †E-mail: sabrina.rodriguez@ulg.ac.be There are different strategies to reduce BLV prevalence. Eradication by culling of infected animals is not economically sustainable in highly infected regions such as Argentina, US or Japan. Partition and confinement on BLV-infected cows is expensive due to duplication of facilities. Finally, several candidate vaccines based on recombinant viral proteins were unsuccessful to protect from challenge. Facing these failures, we propose a novel strategy based on the use of a live-attenuated BLV provirus. The rationale behind this strategy relies on the deletion of genes required to induce pathogenesis leaving those involved in infectivity, resulting in an attenuated mutant with impaired transmissibility. In a first set of experiments, we show that the mutant is infectious and elicits an efficient immune response in sheep (n=3) and in cows (n=9). Lack of spread to uninfected sentinels further supports the safety of the vaccine. Based on these promising results, a validation program in herd (n=105) is ongoing to evaluate the capacity of the candidate vaccine to protect from wild-type BLV infection. The following experiments are carried out: quantification of the proviral loads, assessment of immune response efficiency (antibody titers, CTL response and cytokine profiling), measure of viral expression in vivo (qRT-PCR) and ex vivo (expression of Tax and p24gag) and determination of provirus clonality during infection. This data will be instrumental for understanding the basic mechanisms undergoing during BLV infection and for elaborating of a novel vaccine. [less ▲]

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