Calculating the Rate of CTL Killing

<p>We need to know how important CTLs are in the control of HIV-1 infection, but it is not possible to measure the rate at which CTLs kill HIV-1–infected cells in vivo using conventional assays. Here we develop an alternative approach. CTL selection pressure drives viral escape, so a surrogate marker of the importance of CTLs is the rate at which CTL escape variants replace the wild-type. (A) In a host bearing the restricting HLA allele a CTL escape variant grows more rapidly than and replaces the wild-type because it is subject to a lower rate of CTL killing. The rate of replacement of the wild-type by the escape variant, “the escape rate,” is equal to the difference in growth rate of the wild-type and escape variant. If everything else were equal, the difference in growth rate would be equal to the difference in the CTL killing rate of the wild-type and the escape variant. This would mean that the CTL pressure on the specific epitope that has undergone mutation (the “escape epitope”) could be measured by the escape rate. However, everything else is not equal. Many escape variants will carry a fitness cost, which will slow the growth rate of the escape variant and thus decrease the escape rate. This fitness cost is revealed as the reversion rate when the variant is transferred to a host who does not bear the restricting HLA (B). The escape rate will therefore be equal to the rate of lysis by CTLs targeting the escape epitope minus the fitness cost. Expressed in a different way, the rate of lysis of HIV-1–infected cells by CTLs targeting the escape epitope is equal to the escape rate plus the reversion rate. In (A) the relative position of the two lines “strong CTL pressure, high fitness cost” and “weak CTL pressure, low fitness cost” could be interchanged depending on the magnitude of the differences in CTL strength and variant fitness.