Figure 4.

Effect of signal peptide (SP) modification/replacement on envelope (Env). (A) The HIV-1 SP is responsible for targeting the nascent glycoprotein 160 (gp160) precursor to the endoplasmic reticulum (ER) for processing. Uniquely, the SP remains attached to this protein throughout the ER and is cleaved prior to delivery of gp160 to the Golgi apparatus. Further retention of the SP results in lysosomal degradation of Env and serves as a quality control mechanism. (B) Mutations at specific residues within the N-terminal region of the HIV-1 SP result in alterations to Env expression, glycosylation, DC-SIGN-mediated transinfection, antigenicity, and neutralization. (C, top) Replacement of the native HIV-1 SP with heterologous HIV-1 SPs alters glycosylation, Env recognition by monoclonal antibodies (mAbs), and virus neutralization. Replacement with non-HIV-1 SPs is a common strategy for increasing immunogen yield. However, this approach may also have detrimental effects on Env glycosylation, structure, and antigenicity. The perceived advantage of increased soluble protein yields may be offset by a higher proportion of Env immunogens with under-processed glycans due to the absence of HIV-1 SP-mediated effects on processing. (C, bottom) The glycosylation profiles of HIV-1 glycoprotein 120 (gp120) proteins are dependent on their SPs. Transposition of SPs from HIV-1 species with different proportions of glycan types is sufficient to alter glycosylation profiles.