On the relative fitness of early and late stage Simian immunodeficiency virus isolates

Simian immunodeficiency virus (SIV) has been shown to evolve from a relatively slowly replicating and mildly cytopathic virus early in the infection (SIVMneCL8) to a faster replicating and more cytopathic virus at later stages of the infection (SIVMne170). It has recently been demonstrated that the early and mildly cytopathic variant SIVMneCL8 out-competed the late and highly cytopathic strain SIVMne170 in cell culture experiments, because the fitness disadvantage derived from the higher cytopathicity was not matched by a sufficient increase in the viral replication rate. However, in another set of experiments where the life span of cells in culture was artificially limited, the late and more cytopathic virus won the competition, because under this condition cytopahticity was not an important determinant of viral fitness. It was hypothesized that the limited life span experiment reflected the immune-mediated high turnover environment in vivo more accurately, and that the presence of immune responses accounts for the selection of the cytopathic strain SIVmne170 during later stages of the infection. This paper investigates the effect of immune responses, in particular cytotoxic T lymphocyte (CTL) responses, on the competition dynamics between these two SIV strains with the help of mathematical models. Model analysis and parameter estimates derived from previously published data on SIV growth kinetics suggest that the SIV-specific CTL response might not be the driving force that leads to the selection of the cytopathic strain SIVMne170 during later stages of the infection. This implies that more complex evolutionary mechanisms might have to be invoked in order to explain the emergence of these strains in vivo. One possibility is that the ability of multiple virus particles to infect the same cell (coinfection) might be a pre-requisite for the emergence of the cytopathic strain SIVMne170 as the disease progresses.