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Conference
"Viral Fitness" Prof. Mark Wainberg (biography) English - 2002-04-14 - 33 minutes
Summary : Viral fitness generally refers to the relative replication competence of a virus under defined circumstances. Since viral fitness is generally assessed in tissue culture systems, its relevance to the clinical situation may be difficult to fully establish. At the same time, inferences about the relative fitness or replication competence of different types of viruses can often be derived from clinical trial data and particularly from determinations of levels of plasma viremia. In tissue culture, the ability of any given strain of HIV to replicate may be somewhat dependent on the types of cells that are used for viral propagation in the first place. Hence, certain cell types may display greater or lesser degrees of receptiveness for given viral strains. In some cases, this may be a reflection of co-receptor utilization by a particular viral subtype and, hence, the determinants of fitness can be varied and can include considerations of co-receptor usage. Drug resistance-conferring mutations have also been shown to impact on viral fitness and many have argued that any individual resistance-conferring mutation must, by definition, be one that impairs fitness since, otherwise, these mutated varieties should appear in the absence of treatment as wild-type. However, this interpretation may be overly simplistic because it fails to take into account how individual mutations may impact on one another to alter viral phenotype. As an example, plasma viremia data suggest that the 184V mutation in reverse transcriptase that confers high-level resistance to lamivudine can impact negatively on viral fitness. At the same time, the simultaneous presence of other mutations in reverse transcriptase may cause a reversion to wild-type replication kinetics and overcome any deficit in this regard.
Viral fitness can be directly assessed in tissue culture systems by several methods. One of these involves a recombinant assay in which viral genomic material is transfected into host cells that are then replicated and assessed for their ability to yield progeny virus in comparison to transfection with constructs that would normally encode a wild-type virus. A different method is the simultaneous replication within a single culture of different types of purified cloned viruses that may be studied at different proportions at the time of infection. Genetic sequencing can subsequently establish which of the viruses added to these cultures was the most fit or robust in terms of ability to grow out to high titer. The clinical validation of fitness as a concept in surrogate monitoring of patients with HIV disease is compelling but has still not been fully validated. The latter will require that assessments of fitness be built into prospective clinical trials that may be randomized to include patients receiving different types of drug regimens or who have different mutational profiles responsible for resistance to various antiviral drugs. It may also be premature to equate diminished fitness, in the context of a virus harboring certain drug resistance mutations, with diminished pathogenesis or virulence. Indeed, it is possible to contemplate that viruses may, on occasion, sacrifice a degree of replication competence without necessarily losing their ability to cause serious disease. Finally, compensatory mutations may emerge over time in the viral genome that result in increased replication efficiency.
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