Marek's disease herpesvirus: a model of vaccine-dependent adaptation.

Marek's disease (MD) virus (MDV) is an alphaherpesvirus that causes a rapid-onset T-cell lymphoma in chickens. In order to preserve the viability of poultry industry, non sterilizing vaccines have been used since fifty years, preventing lymphoma development but leading to an imperfect control of MD. Vaccination has been accompanied with the increase in virulence of MDV forcing the development of new vaccine formulations. Several loci of MDV genome are variable and have evolved in link with virulence of MDV strains. It has been shown that MDV is in fact constituted by a dynamic population of genetic variants with a distribution linked to viral strain phenotype. In this context, we have shown that CVI988/Rispens vaccine, still the most efficient one against hypervirulent MDV strains, is composed of twenty variants, variable from one batch to another, evolving likely as RNA virus quasispecies.

Vaccine and oncogenic strains of gallid herpesvirus 2 contain specific subtype variations in the 5' region of the latency-associated transcript that evolve in vitro and in vivo.

Gallid herpesvirus 2 (GaHV-2) is the alphaherpesvirus responsible for Marek's disease (MD), a T-cell lymphoma of chickens. The virulence of the GaHV-2 field strain is steadily increasing, but MD is still controlled by the CVI988/Rispens vaccine. We tried to determine distinguishing traits of the CVI988/Rispens vaccine by focusing on the 5' end region of the latency-associated transcript (5'LAT). It includes a variable number of 60-bp tandem repeats depending on the GaHV-2 strain. By analyzing six batches of vaccine, we showed that CVI988/Rispens consisted of a population of 5'LAT molecular subtypes, all with deletions and lacking 60-bp tandem repeat motifs, with two major subtypes that probably constitute CVI988/Rispens markers. Serial passages in cell culture led to a substantial change in the frequency of CVI988/Rispens 5'LAT subtypes, with non-deleted subtypes harboring up to four 60-bp repeats emerging during the last few passages. Dynamic changes in the distribution of 5'LAT-deleted subtypes were also detected after infection of chickens. By contrast, the 5'LAT region of the oncogenic clonal RB-1B strain, which was investigated at every step from the isolation of the clonal bacmid RB-1B DNA to the isolation of the ovarian lymphoma cell line, consisted of non-deleted 5'LAT subtypes harboring at least two 60-bp repeats. Thus, vaccine and oncogenic GaHV-2 strains consist of specific populations of viral genomes that are constantly evolving in vivo and in vitro and providing potential markers for epidemiological surveys.