Quantifying the Impact of Human Immunodeficiency Virus-1 Escape From Cytotoxic T-Lymphocytes

HIV-1 escape from the cytotoxic T-lymphocyte (CTL) response leads to a weakening of viral control and is likely to be detrimental to the patient. To date, the impact of escape on viral load and CD4+ T cell count has not been quantified, primarily because of sparse longitudinal data and the difficulty of separating cause and effect in cross-sectional studies. We use two independent methods to quantify the impact of HIV-1 escape from CTLs in chronic infection: mathematical modelling of escape and statistical analysis of a cross-sectional cohort. Mathematical modelling revealed a modest increase in log viral load of 0.051 copies ml−1 per escape event. Analysis of the cross-sectional cohort revealed a significant positive association between viral load and the number of “escape events”, after correcting for length of infection and rate of replication. We estimate that a single CTL escape event leads to a viral load increase of 0.11 log copies ml−1 (95% confidence interval: 0.040–0.18), consistent with the predictions from the mathematical modelling. Overall, the number of escape events could only account for approximately 6% of the viral load variation in the cohort. Our findings indicate that although the loss of the CTL response for a single epitope results in a highly statistically significant increase in viral load, the biological impact is modest. We suggest that this small increase in viral load is explained by the small growth advantage of the variant relative to the wildtype virus. Escape from CTLs had a measurable, but unexpectedly low, impact on viral load in chronic infection.Author Summary: HIV, like many viruses, has evolved multiple strategies to evade immune surveillance. One of these strategies is the evolution of escape mutations which reduce the ability of the immune response to kill HIV-infected cells. But does HIV escape matter? Some believe that the accumulation of escape mutations leads to AIDS; many more believe escape is likely to be highly detrimental to human health. Yet, to date, it has not been possible to measure the impact of escape. We developed two independent methods to quantify the impact of escape on HIV viral load. Both methods showed that escape does lead to a detectable increase in viral load, but is unlikely to have a major impact on patient health as the increase is small. Indeed, only 6% of between-individual variation in viral load could be attributed to HIV escape. This work suggests that the current research focus on escape in chronic HIV infection might be out of proportion to its importance with other factors playing a more significant role in determining viral load.