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Proximal Glycans Outside of the Epitopes Regulate the Presentation of HIV-1 Envelope gp120 Helper Epitopes¹

Hualin Li^*, Chong-Feng Xu, Steven Blais, Qi Wan^*, Hui-Tang Zhang, Samuel J. Landry and Catarina E. Hioe^2,*

^* Department of Veterans Affairs New York Harbor Healthcare System and Department of Pathology, Department of Pharmacology and Kimmel Center for Biology and Medicine, Skirball Institute, and Department of Biochemistry, New York University School of Medicine, New York, NY 10016; and Department of Biochemistry, Tulane University Health Sciences Center, New Orleans, LA 70112

Glycosylation of HIV-1 envelope gp120 determines not only the proper structure, but also the immune responses against this Ag. Although glycans may be part of specific epitopes or shield other epitopes from T cells and Abs, this study provides evidence for a different immunomodulatory function of glycans associated with gp120 residues N230 and N448. These glycans are required for efficient MHC class II-restricted presentation of nearby CD4 T cell epitopes, even though they are not part of the epitopes. The glycans do not affect CD4 T cell recognition of more distant epitopes and are not essential for the proper folding and function of gp120. Data on CD4 T cell recognition of N448 mutants combined with proteolysis analyses and surface electrostatic potential calculation around residue N448 support the notion that N448 glycan near the epitope’s C terminus renders the site to be surface accessible and allows its efficient processing. In contrast, the N230 glycan contributes to the nearby epitope presentation at a step other than the proteolytic processing of the epitope. Hence, N-glycans can determine CD4 T cell recognition of nearby gp120 epitopes by regulating the different steps in the MHC class II processing and presentation pathway after APCs acquire the intact gp120 Ag exogenously. Modifications of amino acids bearing glycans at the C termini of gp120 helper epitopes may prove to be a useful strategy for enhancing the immunogenicity of HIV-1 envelope gp120.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This study was supported by funds from a Merit Review Award and the Research Enhancement Award Program of the U.S. Department of Veterans Affairs, the New York University Center for AIDS Research Immunology Core (Grant AI-27742), the Training Program in Tuberculosis and HIV Prevention and Treatment (Grant D43 TWO1409), the Louisiana Vaccine Center and South Louisiana Institute for Infectious Disease Research, and by National Institutes of Health Grant AI-48371. The mass spectrometry analysis was supported in part by National Institutes of Health Grants NS-050276 and RR-14662 to Dr. Thomas A. Neubert (Skirball Institute, New York University School of Medicine).

² Address correspondence and reprint requests to Dr. Catarina E. Hioe, Veterans Affairs Medical Center, 423 East 23rd Street, Room 18-124 North, New York, NY 10010. E-mail address: catarina.hioe{at}nyumc.org

³ Abbreviations used in this paper: WT, wild type; MS, mass spectrometry; LC, liquid chromatography; ESI, electrospray ionization; sCD4, soluble CD4.

⁴ The online version of this article contains supplemental material.