Variable constraints on the principal immunodominant domain of the transmembrane glycoprotein of human immunodeficiency virus type 1

Lentiviruses have in their transmembrane glycoprotein (TM) a highly immunog enic structure referred to as the principal immunodominant domain (PID), Th e PID forms a loop of 5 to 7 amino acids between two conserved cysteines. P revious studies showed that envelope (Env) glycoprotein functions of feline immunodeficiency virus (FIV) could be retained after extensive mutation of the PID loop sequence, in spite of its high conservation. In order to comp are Env function in different lentiviruses, either random mutations were in troduced in the PID loop sequence of human immunodeficiency virus type 1 (H IV-1) or the entire HIV-1 PID loop was replaced by the corresponding PID lo op of FIV or simian immunodeficiency virus (SN). In the macrophage-tropic H IV-1 ADA Env, mutations impaired the processing of the gp160 Env precursor, thereby abolishing viral infectivity. However, 6 of the 108 random Env mut ants that were screened retained the capacity to induce cell membrane fusio n. The SIV and FIV sequences and five random mutations were then introduced in the context ofT-cell-line-adapted HIV-1 LAI which, although phenotypica lly distant from HIV-1 ADA, has an identical PID loop sequence. In contrast to the situation for HIV-1 ADA mutants, the cleavage of the Env precursor was unaffected in most HIV-1 LAI mutants. Such mutations, however; resulted in increased shedding of the gp120 surface glycoprotein (SU) from the gp41 TM. The HIV-1 LAI Env mutants showed high fusogenic efficiency, Three Env mutants retained the capacity to mediate virus entry in target cells, altho ugh less efficiently than the wild-type Env, and allowed the reconstitution of infectious molecular clones. These results indicated that in HIV-1, lik e FIV, the conserved PID sequence can be changed without impairing Env func tion. However, functional constraints on the PID of HIV-1 vary depending on the structural context of Env, presumably in relation to the role of the P ID in the interaction of the SU and TM subunits and the stability of the En v complex.