Multiple domains of the SIV Env protein determine virus replication efficiency and neutralization sensitivity

SIVmac239 and SIVmac1A11 are wild-type viruses encoding Env proteins with full-length or truncated cytoplasmic tails (CTs), respectively. A mutant designated SIVmac239T has a site-specific mutation which introduces a stop codon in the env gene resulting a truncated protein of similar length to SIVmac1A11 Env. To investigate the role of specific sequence differences in these Env proteins, we constructed SIV mutants encoding 1A11 or 239 Env proteins with reciprocal exchanges of the CT or exchanges of both the surface unit (SU) and CT sequences. A truncated CT in the context of the 1A11 SU subunit was found to significantly enhance replication in CEMx174 (human T-cell line) and rhesus PBMCs. However, similar Env CT truncation did not enhance replication of SIVmac239 in human or monkey cells. SIVmac1A11 with a full-length SIVmac239 CT did not replicate in human T-cell lines, but truncation of the CT by a stop codon resulted in replication. We also observed that these viruses differed significantly in sensitivity to neutralization by antibody. Taken together, the results indicated that the length of the CT domain as well as specific sequence differences in the SU domain affect viral replication capacity as well as sensitivity to neutralization.