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properties of the fitness trajectories. The model has two main properties: mean fitness evolves rapidly during the first passages and asymptotically approaches a maximum value. The reason for the deceleration in the rate of adaptation has to do with the availability of beneficial mutations and the magnitude associated with each available mutation. At the beginning of the process, when the viral population is far from the optimum, any beneficial mutation will increase fitness by driving it upward in a fitness landscape (Orr, 1998). However, as the population approaches the fitness peak, only fine-tuning mutations, less abundant than the former, will be needed. Once the virus becomes adapted to its new environment, no further improvement is expected unless the environment changes.

The issue regarding fitness changes also should be considered when viruses shift among environments. Three types of in vitro experiments have been done in relation to environmental changes. First, experiments of adaptation of VSV to new hosts (Holland et al., 1991; Novella et al., 1999) has been done. VSV clones, previously adapted to BHK cells, gained fitness after few passages on alternative new host cells. It is controversial, however, if VSV also concurrently increased fitness on ancestral BHK cells. This question needs to be addressed under appropriate and more replicated experiments. Second, the fitness changes associated with adaptation to fluctuating environments also were explored. Experiments have been done with VSV and Eastern equine encephalitis virus (Novella et al., 1999; Weaver et al., 1999), where viruses were grown in two new cell types, changing daily. Both viruses were selected with increased fitness in both novel environments. Adaptation seems, however, to be reversible. VSV clones adapted to persistently replicate in LL5 insect cells showed low fitness on BHK cells and in mouse brain (Novella et al., 1995), but attenuated virus soon recovered fitness and virulence after a few passages back in BHK. Third, in vitro experiments were performed with antiviral agents added to the media. When cells were treated with α-interferon, the size of VSV viral populations experienced a dramatic reduction (99.9%). Those viruses that developed α-interferon resistance quickly increased their fitness in the presence of the interferon (Novella et al., 1996). However, fitness decreased when interferon was removed from the media.

Another question that could be of great importance to viral populations is its eventual differentiation into subpopulations (for instance different organs or tissues within an individual), and then subsequent migration among subpopulations. We have experimentally modeled this situation by means of an in vitro system to simulate migration of VSV among isolated homogeneous host cell populations (see Miralles et al., 1999 for a detailed description of the experimental protocol). The results clearly demonstrated a positive correlation between migration rate and



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