Evolution of coreceptor use and CD4-independence in envelope clones derived from SIVsm-infected macaques

Coreceptor use of HIV can evolve during infection. We previously examined coreceptor use of related SIVsm inoculum viruses and sequential reisolates from cynomolgus macaques. These viruses exhibited broad coreceptor specificities and, generally, CCR5 use remained efficient and stable, while alternative coreceptor use decreased longitudinally. Here we demonstrate that individual envelopes (Envs) from inoculum and reisolate viruses fuse via a range of coreceptors, including CCR5, CCR8, CXCR6, GPR15, GPR1, and APJ. On the whole, coreceptor use of Envs from sequential reisolates recapitulated that of reisolate viruses, thus CCR5 use remained stable while alternative coreceptor use tended to decrease over time. Rhesus CCR5, GPR15, and CXCR6 supported fusion to a similar extent as their human counterparts. Additionally, a number of Envs mediated CD4-independent fusion via CCR5 and GPR15. Envs from different inoculum viruses exhibited distinct dependencies on CD4 for fusion via CCR5, ranging from strictly CD4-dependent to efficiently CD4-independent. Early reisolates from macaques infected with CD4-independent inoculums maintained or evolved Envs with a broad range of CD4-independence. CD4-independence became less variable/efficient in late reisolates from macaques that developed neutralizing antibodies. Infection with a CD4-dependent virus resulted in evolution of CD4-independent Envs in late reisolates. While CD4 independence can potentially broaden tropism in vivo, CD4-independent viruses are particularly sensitive to neutralizing antibodies. Therefore, interplay between receptor tropism and neutralization may shape viral evolution and SIV pathogenesis.