BioProject

Primate lentiviruses, including human immunodeficiency virus type 1 (HIV-1) type 2 (HIV-2) and the simian immunodeficiency viruses (SIVs), cause infections that result in persistent lifelong viral replication in the host despite the presence of virus-specific adaptive immune responses. Rapid replication kinetics coupled with a high mutation rate generate a large population of genetically distinct variants that allows for escape from host immune responses, including antibodies targeting the viral envelope glycoprotein (Env). We examined the evolutionary dynamics of the SIV env gene during early infection (< 29 weeks post-infection) in a cohort of four SIVmac251-infected rhesus macaques. Three animals mounted detectable Env-specific antibody responses while a fourth one, with high viral loads and rapid disease progression, did not. Using ultra-deep sequencing of the viral populations, we tracked env evolution during acute and early post-acute infection (from 2-29 weeks post-infection) capturing a transmission bottleneck and the subsequent reestablishment of Env diversity, including the appearance and fixation of substitutions, insertions, and deletions in each animal. A majority of changes in the gp120 subunit mapped to two short clusters of 9-12 codons, one in the first variable region (V1) and one in V4, while most of the changes in the gp41 subunit appeared in the cytoplasmic tail. Changes in V4 included multiple closely-spaced in-frame deletions, which dominated the viral population in two animals with antibody responses to Env. Single point substitutions in V1 and V4 that emerged during early infection did not alter viral replicative fitness when tested using a novel high-resolution viral competition assay, while a frequent 8-amino-acid deletion in V4 did incur a replicative fitness cost. Our results, together with the observation that very similar or identical patterns of sequence evolution also occur in different macaque species infected with related but divergent strains of SIV, suggest that resistance to early, strain-specific anti-Env antibodies is the result of temporally and mutationally predictable pathways of escape that occur during the early stages of infection.