Equine infectious anemia virus genomic evolution in progressor and nonprogressor ponies

A primary mechanism of lentivirus persistence is the ability of these virus es to evolve in response to biological and immunological selective pressure s with a remarkable array of genetic and antigenic variations that constitu te a perpetual natural experiment in genetic engineering. A widely accepted paradigm of lentivirus evolution is that the rate of genetic variation is correlated directly with the levels of virus replication: the greater the v iral replication, the more opportunities that exist for genetic modificatio ns and selection of viral variants. To test this hypothesis directly, we ex amined the patterns of equine infectious anemia virus (EIAV) envelope varia tion during a 2.5-year period in experimentally infected ponies that differ ed markedly in clinical progression and in steady-state levels of viral rep lication as indicated by plasma virus genomic RNA assays. The results of th ese comprehensive studies revealed for the first time similar extents of en velope gp90 variation in persistently infected ponies regardless of the num ber of disease cycles tone to six) and viremia during chronic disease. The extent of envelope variation was also independent of the apparent steady-st ate levels of virus replication during long-term asymptomatic infection, va rying from undetectable to 10(5) genomic RNA copies per mi of plasma. In ad dition, the data confirmed the evolution of distinct virus populations (gen omic quasispecies) associated with sequential febrile episodes during acute and chronic EIA and demonstrated for the first time ongoing envelope varia tion during long-term asymptomatic infections, Finally, comparison of the r ates of evolution of the previously defined EIAV gp90 variable domains demo nstrated distinct differences in the rates of nucleotide and amino acid seq uence variation, presumably reflecting differences in the ability of differ ent envelope domains to respond to immune or other biological selection pre ssures. Thus, these data suggest that EIAV variation can be associated pred ominantly with ongoing low levels of virus replication and selection in tar get tissues, even in the absence of substantial levels of plasma viremia, a nd that envelope variation continues during all stages of persistent infect ion as the virus successfully avoids clearance by host defense mechanisms.