Mutational analysis of the internal membrane proximal domain of the HIV glycoprotein C-terminus

This study focuses on the long stretch of highly conserved amino acids in the membrane proximal part of the HIV-1 cytoplasmic tail (Env amino acids (aa) 706–718) upstream of the overlap with the tat and rev second coding exons. Changes in Env aa 713 and 715, although they did not affect Env function, abrogated replicative spread. Other amino acid substitutions, i.e., 706–712, 714 and 716, despite their conservation, did not result in defective replicative phenotypes even in primary peripheral blood lymphocytes. Our results point to their involvement in presently unrecognized essential Env functions pertinent only in in vivo. Interestingly, changes in the codons for residues 717–718 as well as some mutations in residues 714–716 abrogated Gag expression but still allowed expression of functional Env in a rev-independent manner. This could be due to the inactivation of a rev-regulated negative element within the respective nucleotide sequence (8354–8368).

► Specific mutations in Env-CT abrogate replicative spread.
► Changes in highly conserved Env-CT residues do not affect infectivity in PBMCs.
► Specific mutation results in abrogated HIV Gag but rev-independent Env expression.
► Inactivation of HIV rev-regulated negative sequence element.