Title : Distinct mechanisms regulate the exposure of broadly neutralizing antibody epitopes on HIV-1 particles
Abstract:
Background: Despite extensive research, an effective prophylactic vaccine against HIV-1 remains elusive. Currently, substantial focus is directed toward developing vaccines that can induce broadly neutralizing antibodies (bNAbs) capable of neutralizing multiple HIV-1 strains. However, HIV-1 employs various strategies to conceal the cross-reactive and conserved epitopes targeted by these bNAbs, resulting in an inadequate and non-protective immune response.
Dr. Chitra Upadhyay received her PhD degree in 2003 from India. She then and moved to USA in 2005 for her postdoctoral training. She took a career break from 2009-2012 to raise her family and later she joined NYU Langone Medical Center for a second post-doc. In 2015 she joined Icahn School of Medicine at Mount Sinai as an Instructor after which in 2017 she obtained the position of Assistant Professor at the same institution. Her research primarily focusses on HIV-1 pathogenesis and vaccine development. This study aimed to map the antigenic landscape of HIV-1 envelope (Env) on virions and identify mechanisms to expose these epitopes.
Methods and Results: To achieve our goal, we designed a flow cytometry-based assay capable of detecting antibody binding on virus particles. Using three HIV-1 isolates and a panel of monoclonal antibodies (mAbs), we demonstrated that specific epitopes—such as V2i, gp120-g41 interface, and gp41-MPER—are accessible by mAbs, while others (V3, V2q, and CD4bs) remain hidden. Prolonging virus-mAb interaction did not unmask these epitopes, but allosteric changes induced by pre-binding of specific mAbs rendered them accessible. This led us to explore whether similar changes are necessary for bNAbs to neutralize the virus. To test this, we assessed HIV-1 neutralization under two conditions: incubating the virus-mAb mix or not before adding target TZM.bl cells. Interestingly, both conditions yielded similar neutralization levels, suggesting that the interaction between virus and target cells sensitizes the virions for neutralization via bNAbs. Additionally, we found that lectin-glycan interactions can also expose these epitopes, with effectiveness depending on lectin specificity.
Conclusion: These findings deepen our understanding of how HIV-1 strategically conceals critical epitopes from the host immune response. They also provide valuable insights for designing potent antibody combinations for therapeutic purposes. Furthermore, these findings pave the way for exploring innovative vaccine regimens involving Env-mAb or Env-lectin complexes. Such regimens have the potential to effectively present bNAb epitopes to the host immune system.
