Synonymous mutations in stem-loop III of Rev responsive elements enhance HIV-1 replication impaired by primary mutations for resistance to enfuvirtide

Primary mutations in HIV-1 that are directly involved in the resistance to enfuvirtide have been well documented. However, secondary mutations that are associated with primary mutations and contribute little to the resistance still remain to be elucidated. This study reveals that synonymous mutations at gp41 Q41 (CAG to CAA) or L44 (UUG to CUG) act as secondary mutations. Complementary mutations in the nucleotide level are located in the Rev responsive element (RRE) of the HIV-1 RNA-genome and maintain the replication kinetics of HIV-1 through increasing the structural stability of stem-loop III in the RRE. Therefore, synonymous mutations in the gp41/RRE sequence improve the viral replication impaired by the primary mutations and play a key role as secondary (complementary) mutations.