Time intervals in sequence sampling, not data modifications, have a major impact on estimates of HIV escape rates

Abstract

The ability of HIV to avoid recognition by humoral and cellular immunity (viral escape) is well documented but the strength of the immune response needed to cause such a viral escape remains poorly quantified. Several previous studies observed a more rapid escape of HIV from CD8 T cell responses in the acute phase of infection as compared to the chronic infection. With the help of simple mathematical models the rate of HIV escape was estimated and results were interpreted to suggest that CD8 T cell responses causing escape in acute HIV infection may be more efficient at killing virus-infected cells than responses that cause escape in chronic infection, or alternatively, early escapes occur in epitopes mutations in which there is minimal fitness cost to the virus. These conclusions, however, were challenged on several grounds, including linkage and interference of multiple escape mutations due to a low population size and because of potential issues associated with modifying the data to estimate escape rates. Here we use a parametric resampling method which does not require data modification to show that previous results on the decline of the viral escape rate with time since infection remain unchanged. However, using this method we also show that estimates of the escape rate are highly sensitive to the time interval between measurements with longer intervals biasing estimates of the escape rate downwards. Our results thus suggest that data modifications for early and late escapes were not the primary reason for the observed decline in the escape rate with time since infection. However, longer sampling periods for escapes in chronic infection strongly influence estimates of the escape rate. More frequent sampling of viral sequences in the chronic infection may improve our understanding of factors influencing the rate of HIV escape from CD8 T cell responses.