Isolation and structure of broad SIV-neutralizing antibodies reveal a proximal helical MPER epitope recognized by a
Jason Gorman1, Renguang Du2, Yen-Ting Lai2
1Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA; Division of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993, USA.
Abstract:
The membrane-proximal external region (MPER) of the HIV-1 envelope is a target for broadly neutralizing antibodies (bnAbs), and vaccine-elicited MPER-directed antibodies have recently been reported from a human clinical trial. In this study, we sought to identify MPER-directed nAbs in simian immunodeficiency virus (SIV)-infected rhesus macaques. We isolated four lineages of SIV MPER-directed nAbs from two SIV-infected macaques. The nAbs displayed low potency but up to 90% breadth on a 20-strain SIV panel. Crystal structures of representative nAbs in complex with SIV MPER peptides revealed the SIV antibodies to bind a helical epitope at the N-terminal (proximal) region of the MPER, defining a reproducible multi-donor class encompassing all four lineages. HIV-1 comparison showed that this class of SIV MPER-directed antibodies targets a helical region overlapping that targeted by human vaccine-elicited ones. Thus, a prevalent and reproducible class of SIV bnAbs recognizes an epitope similar to that recently observed in an HIV-1-vaccine trial.
Insights
Researchers identified broadly neutralizing antibodies (bnAbs) targeting the SIV membrane-proximal external region (MPER) in macaques. These SIV bnAbs recognize a similar epitope to those found in HIV-1 vaccine trials.
Area of Science:
- Immunology
- Virology
- Structural Biology
Background:
- The membrane-proximal external region (MPER) of the HIV-1 envelope is a key target for broadly neutralizing antibodies (bnAbs).
- MPER-directed antibodies elicited by vaccines have shown promise in human clinical trials.
- Identifying similar antibody targets in related viruses like SIV is crucial for vaccine development.
Purpose of the Study:
- To identify broadly neutralizing antibodies (bnAbs) targeting the MPER in simian immunodeficiency virus (SIV)-infected rhesus macaques.
- To characterize the epitope recognized by these SIV MPER-directed bnAbs and compare it to HIV-1 targets.
Main Methods:
- Isolation and characterization of SIV MPER-directed bnAbs from infected macaques.
- Assessment of antibody breadth and potency against a panel of SIV strains.
- Determination of crystal structures of bnAbs in complex with SIV MPER peptides.
Main Results:
- Four lineages of SIV MPER-directed bnAbs were isolated, exhibiting up to 90% breadth across a 20-strain SIV panel.
- Crystal structures revealed these SIV bnAbs bind a helical epitope at the N-terminal MPER region.
- This epitope is similar to the one targeted by human vaccine-elicited antibodies against HIV-1.
Conclusions:
- A prevalent and reproducible class of SIV bnAbs targets a conserved helical epitope within the MPER.
- This finding suggests a conserved antibody target across SIV and HIV-1, relevant for vaccine design.
- The identified epitope represents a promising target for developing effective vaccines against both SIV and HIV-1.
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