Intrahost selection pressures drive rapid dengue virus microevolution in acute human infections

Parameswaran, Poornima; Wang, Chunling; Trivedi, Surbhi Bharat; Eswarappa, Meghana; Montoya, Magelda; Balmaseda, Angel; Harris, Eva

Dengue, caused by four dengue virus serotypes (DENV-1–DENV-4), is a highly-prevalent mosquito-borne viral disease in humans. Yet, selection pressures driving DENV microevolution within human hosts (‘intrahost’) remain unknown. We employed a whole-genome segmented amplification approach coupled with deep sequencing to profile DENV-3 intrahost diversity in peripheral blood mononuclear cell (PBMC) and plasma samples from 77 dengue patients. DENV-3 intrahost diversity appears to be driven by immune pressures as well as replicative success in PBMCs and potentially other replication sites. Hotspots for intrahost variation were detected in 59–78% of patients in the viral Envelope and pre-Membrane/Membrane proteins, which together form the virion surface. Dominant variants at the hotspots arose via convergent microevolution, appear to be immune-escape variants, and were evolutionarily constrained at the macro-level due to viral replication defects. Dengue is thus an example of an acute infection in which selection pressures within infected individuals drive rapid intrahost virus microevolution.