Alterations of HIV-1 envelope phenotype and antibody-mediated neutralization by signal peptide mutations—Upadhyay 2018

HIV-1 enters host cells via Env. HIV-1 Env, like other membrane-bound and secreted proteins, has an N-terminal signal peptide (SP) that sends the nascent Env to the endoplasmic reticulum (ER) for synthesis and post-translational modifications. SP is cleaved during Env biosynthesis but may affect its phenotype. HIV-1 isolates have substantial Env SP sequence diversity, although its relevance is uncertain. We hypothesize that Env SP alterations affect ER-Golgi secretory route transport, folding, and glycosylation, which affects Env incorporation into virions, receptor binding, and antibody recognition. Mutating charged residues in the Env SP in infectious molecular clone HIV-1 REJO.c/2864 was first tested. Three mutations impacting histidine at position 12 altered Env integration into virions and reduced virus infectivity and DC-SIGN-mediated virus capture and transmission. Mutations at locations 8, 12, and 15 made the virus more resistant to Env V1V2 monoclonal antibodies. Env reactivity with certain lectins and mass spectrometry showed that these mutations changed N-glycan oligosaccharide composition. Similar alterations increased neutralization resistance and N-glycan composition in another HIV-1 strain, JRFL. This is the first study to reveal that HIV-1 Env SP residues modulate Env N-glycan oligosaccharide moieties to influence virus neutralization sensitivity. Thus, HIV-1 Env SP sequences may be selected to balance virus infectiousness with host antibody resistance. 289 words.

Upadhyay, C., Feyznezhad, R., Yang, W., Zhang, H., Zolla-Pazner, S., & Hioe, C. E. (2018). Alterations of HIV-1 envelope phenotype and antibody-mediated neutralization by signal peptide mutations. PLoS pathogens, 14(1), e1006812. https://doi.org/10.1371/journal.ppat.1006812