ADAPTIVE EVOLUTION OF THE SIV ENV PROTEIN REFLECTS VIRUS-SPECIFIC ANTIBODY RESPONSES DURING PERSISTENT INFECTION
Sergio Ita, Welkin Johnson
1Harvard Medical School, Boston, MA, 2Boston College, Chestnut Hill, MA.
Primate lentiviruses including HIV-1, 2, and SIVs cause persistent lifelong infections despite the presence of virus-specific adaptive immune responses. The target of antibodies is the viral envelope glycoprotein (Env) which is expressed on the surface of virions and infected cells. SIV env sequence variation arising from evasion of antibodies is well known, yet the evolution of escape within hosts is poorly understood and, whether these adaptations exact a fitness cost, is not well defined. We sequenced longitudinal samples (2 - 29 weeks post infection) from 4 SIV-infected rhesus macaques to reconstruct SIV env sequence evolution starting from a defined stock inoculum using high-resolution next-generation sequencing (NGS). By NGS analysis, we captured a population bottleneck at the point of transmission from the stock into each animal and the subsequent emergence of Env diversity from the initially homogeneous population that correlated with the onset of Env-specific antibodies. We tracked selection of mutations, in-frame insertions, and deletions of the viral populations in each animal and found that changes were highly concentrated at multiple sites in surface-exposed variable loops. The deterministic appearance of changes leading to replacement of the residue present at transmission, polymorphism, and insertion/deletions revealed a remarkable degree of viral protein evolvability. The observation that similar or identical changes occurred in multiple animals suggests SIV Env relies on specific sequence pathways to evade continuous antibody targeting. We engineered selected adaptations into full length virus to now determine whether these mutations incur a replicative fitness cost using a deep sequencing-based viral fitness assay.