HIV-1 Envelope Glycoproteins Proteolytic Cleavage Protects Infected Cells from ADCC Mediated by Plasma from Infected Individuals
- PMID: 34835042
- PMCID: PMC8625184
- DOI: 10.3390/v13112236
HIV-1 Envelope Glycoproteins Proteolytic Cleavage Protects Infected Cells from ADCC Mediated by Plasma from Infected Individuals
Abstract
The HIV-1 envelope glycoprotein (Env) is synthesized in the endoplasmic reticulum as a trimeric gp160 precursor, which requires proteolytic cleavage by a cellular furin protease to mediate virus-cell fusion. Env is conformationally flexible but controls its transition from the unbound "closed" conformation (State 1) to downstream CD4-bound conformations (States 2/3), which are required for fusion. In particular, HIV-1 has evolved several mechanisms that reduce the premature "opening" of Env which exposes highly conserved epitopes recognized by non-neutralizing antibodies (nnAbs) capable of mediating antibody-dependent cellular cytotoxicity (ADCC). Env cleavage decreases its conformational transitions favoring the adoption of the "closed" conformation. Here we altered the gp160 furin cleavage site to impair Env cleavage and to examine its impact on ADCC responses mediated by plasma from HIV-1-infected individuals. We found that infected primary CD4+ T cells expressing uncleaved, but not wildtype, Env are efficiently recognized by nnAbs and become highly susceptible to ADCC responses mediated by plasma from HIV-1-infected individuals. Thus, HIV-1 limits the exposure of uncleaved Env at the surface of HIV-1-infected cells at least in part to escape ADCC responses.
Keywords: ADCC; CD4 mimetics; Env glycoprotein; HIV+ plasma; HIV-1; Temsavir; furin cleavage site; nnAbs.
Conflict of interest statement
The authors declare no competing interest.
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References
-
- Qi M., Williams J.A., Chu H., Chen X., Wang J.J., Ding L., Akhirome E., Wen X., Lapierre L.A., Goldenring J.R., et al. Rab11-FIP1C and Rab14 direct plasma membrane sorting and particle incorporation of the HIV-1 envelope glycoprotein complex. PLoS Pathog. 2013;9:e1003278. doi: 10.1371/journal.ppat.1003278. - DOI - PMC - PubMed
-
- Kirschman J., Qi M., Ding L., Hammonds J., Dienger-Stambaugh K., Wang J.J., Lapierre L.A., Goldenring J.R., Spearman P. HIV-1 Envelope Glycoprotein Trafficking through the Endosomal Recycling Compartment Is Required for Particle Incorporation. J. Virol. 2018;92 doi: 10.1128/JVI.01893-17. - DOI - PMC - PubMed
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