What evolutionary processes or selective pressures might have given rise to lineage B.1.1.7?
High rates of mutation accumulation over short time periods have been reported previously in studies of immunodeficient or immunosuppressed patients who are chronically infected with SARS-CoV-2 (Choi et al. 2020; Avanzato et al. 2020; Kemp et al. 2020). These infections exhibit detectable SARS-CoV-2 RNA for 2-4 months or longer (although there are also reports of long infections in some immunocompetent individuals). The patients are treated with convalescent plasma (sometimes more than once) and usually also with the drug remdesivir. Virus genome sequencing of these infections reveals unusually large numbers of nucleotide changes and deletion mutations and often high ratios of non-synonymous to synonymous changes. Convalescent plasma is often given when patient viral loads are high, and Kemp et al. (2020) report that intra-patient virus genetic diversity increased after plasma treatment was given.
Under such circumstances, the evolutionary dynamics of and selective pressures upon the intra-patient virus population are expected to be very different to those experienced in typical infection. First, selection from natural immune responses in immune-deficient/suppressed patients will be weak or absent. Second, the selection arising from antibody therapy may be strong due to high antibody concentrations. Third, if antibody therapy is administered after many weeks of chronic infection, the virus population may be unusually large and genetically diverse at the time that antibody-mediated selective pressure is applied, creating suitable circumstances for the rapid fixation of multiple virus genetic changes through direct selection and genetic hitchhiking.
These considerations lead us to hypothesise that the unusual genetic divergence of lineage B.1.1.7 may have resulted, at least in part, from virus evolution with a chronically-infected individual. Although such infections are rare, and onward transmission from them presumably even rarer, they are not improbable given the ongoing large number of new infections.
Although we speculate here that chronic infection played a role in the origins of the B.1.1.7 variant, this remains a hypothesis and we cannot yet infer the precise nature of this event.
