Inhibition of human immunodeficiency virus (HIV-1) infectivity by expression of poorly or broadly neutralizing antibodies against Env in virus-producing cells
- PMID: 38289101
- PMCID: PMC10878270
- DOI: 10.1128/jvi.01594-23
Inhibition of human immunodeficiency virus (HIV-1) infectivity by expression of poorly or broadly neutralizing antibodies against Env in virus-producing cells
Abstract
The human immunodeficiency virus (HIV-1) envelope (Env) glycoprotein precursor (gp160) trimerizes, is modified by high-mannose glycans in the endoplasmic reticulum, and is transported via Golgi and non-Golgi secretory pathways to the infected cell surface. In the Golgi, gp160 is partially modified by complex carbohydrates and proteolytically cleaved to produce the mature functional Env trimer, which is preferentially incorporated into virions. Broadly neutralizing antibodies (bNAbs) generally recognize the cleaved Env trimer, whereas poorly neutralizing antibodies (pNAbs) bind the conformationally flexible gp160. We found that expression of bNAbs, pNAbs, or soluble/membrane forms of the receptor, CD4, in cells producing HIV-1 all decreased viral infectivity. Four patterns of co-expressed ligand:Env were observed: (i) ligands (CD4, soluble CD4-Ig, and some pNAbs) that specifically recognize the CD4-bound Env conformation resulted in uncleaved Envs lacking complex glycans that were not incorporated into virions; (ii) other pNAbs produced Envs with some complex carbohydrates and severe defects in cleavage, which were relieved by brefeldin A treatment; (iii) bNAbs that recognize gp160 as well as mature Envs resulted in Envs with some complex carbohydrates and moderate decreases in virion Env cleavage; and (iv) bNAbs that preferentially recognize mature Envs produced cleaved Envs with complex glycans in cells and on virions. The low infectivity observed upon co-expression of pNAbs or CD4 could be explained by disruption of Env trafficking, reducing the level of Env and/or increasing the fraction of uncleaved Env on virions. In addition to bNAb effects on virion Env cleavage, the secreted bNAbs neutralized the co-expressed viruses.IMPORTANCEThe Env trimers on the HIV-1 mediate virus entry into host cells. Env is synthesized in infected cells, modified by complex sugars, and cleaved to form a mature, functional Env, which is incorporated into virus particles. Env elicits antibodies in infected individuals, some of which can neutralize the virus. We found that antibodies co-expressed in the virus-producing cell can disrupt Env transit to the proper compartment for cleavage and sugar modification and, in some cases, block incorporation into viruses. These studies provide insights into the processes by which Env becomes functional in the virus-producing cell and may assist attempts to interfere with these events to inhibit HIV-1 infection.
Keywords: brefeldin A; envelope glycoprotein; glycosylation; intracellular antibody; neutralization; proteolytic cleavage; secretory pathway; soluble CD4; trafficking; virion incorporation.
Conflict of interest statement
The authors declare no conflict of interest.
Similar articles
-
Characterization of the Human Immunodeficiency Virus (HIV-1) Envelope Glycoprotein Conformational States on Infectious Virus Particles.J Virol. 2023 Mar 30;97(3):e0185722. doi: 10.1128/jvi.01857-22. Epub 2023 Feb 23. J Virol. 2023. PMID: 36815832 Free PMC article.
-
Asymmetric Structures and Conformational Plasticity of the Uncleaved Full-Length Human Immunodeficiency Virus Envelope Glycoprotein Trimer.J Virol. 2021 Nov 23;95(24):e0052921. doi: 10.1128/JVI.00529-21. Epub 2021 Sep 22. J Virol. 2021. PMID: 34549974 Free PMC article.
-
Dual Pathways of Human Immunodeficiency Virus Type 1 Envelope Glycoprotein Trafficking Modulate the Selective Exclusion of Uncleaved Oligomers from Virions.J Virol. 2021 Jan 13;95(3):e01369-20. doi: 10.1128/JVI.01369-20. Print 2021 Jan 13. J Virol. 2021. PMID: 33148792 Free PMC article.
-
Hitting the sweet spot: exploiting HIV-1 glycan shield for induction of broadly neutralizing antibodies.Curr Opin HIV AIDS. 2020 Sep;15(5):267-274. doi: 10.1097/COH.0000000000000639. Curr Opin HIV AIDS. 2020. PMID: 32675574 Free PMC article. Review.
-
Development of broadly neutralizing antibodies from autologous neutralizing antibody responses in HIV infection.Curr Opin HIV AIDS. 2014 May;9(3):210-6. doi: 10.1097/COH.0000000000000057. Curr Opin HIV AIDS. 2014. PMID: 24662931 Free PMC article. Review.
References
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Medical
Research Materials