Broad CTL Response in Early HIV Infection Drives Multiple Concurrent CTL Escapes

Recent studies have highlighted the ability of HIV to escape from cytotoxic T lymphocyte (CTL) responses that concurrently target multiple viral epitopes. Yet, the viral dynamics involved in such escape are incompletely understood. Previous analyses have made several strong assumptions regarding HIV escape from CTL responses such as independent or non-concurrent escape from individual CTL responses. Using experimental data from evolution of HIV half genomes in four patients we observe concurrent viral escape from multiple CTL responses during early infection (first 100 days of infection), providing confirmation of a recent result found in a study of one HIV-infected patient. We show that current methods of estimating CTL escape rates, based on the assumption of independent escapes, are biased and perform poorly when CTL escape proceeds concurrently at multiple epitopes. We propose a new method for analyzing longitudinal sequence data to estimate the rate of CTL escape across multiple epitopes; this method involves few parameters and performs well in simulation studies. By applying our novel method to experimental data, we find that concurrent multiple escapes occur at rates between 0.03 and 0.4 day−1, a relatively broad range that reflects uncertainty due to sparse sampling and wide ranges of parameter values. However, we show that concurrent escape at rates 0.1–0.2 day−1 across multiple epitopes is consistent with our patient datasets.Author Summary: Since the early 1990s, cytotoxic T lymphocytes (CTLs) have been known to play an important role in HIV infection with CTLs targeting HIV epitopes and, in turn, HIV escapes arising through mutations in the targeted epitopes. Over the past decade, studies have shown that CTL responses concurrently target multiple HIV epitopes, yet the effect of concurrent responses on HIV dynamics and evolution is not well understood. Through an analysis of patient datasets and a novel statistical method, we show that during early HIV infection concurrent CTL responses drive concurrent HIV escapes at multiple epitopes with significant pressure, suggesting a complex picture in which HIV simultaneously explores multiple mutational pathways to escape from broad and potent CTL response.