Project ID CM-HD2023_10

ThemeCM-HD

Co Supervisor 1A Department of Infectious Diseases/SIMSWebsite

Co Supervisor 1B Department Infectious Diseases / SIMSWebsite

Development of glycan-binding broadly neutralizing antibody responses in HIV-1 infection

An HIV vaccine is urgently needed to prevent new HIV infections worldwide. Approximately 10-30% of HIV infected individuals generate antibodies that are capable of neutralizing a broad range of HIV isolates and these neutralizing antibodies (nAbs) have been shown to protect against SHIV challenge in macaque models. Isolation and characterisation of nAbs has revealed regions of the HIV envelope glycoprotein (Env), gp120/gp41, that are targeted by the host immune response during infection and re-eliciting these nAbs may be a key step for a successful HIV vaccine. Gp120 is heavily glycosylated with host-derived N-linked glycans and although glycans were previously thought to shield conserved protein regions from the immune system, we have shown that many of the most broad and potent HIV nAbs bind directly to glycans highlighting them as important targets for HIV vaccine design [1].

Objectives:
Immunization with recombinant gp120/gp41 does not generate glycan-binding nAbs. Therefore, using unique longitudinal clinical samples from individuals acutely infected with HIV in the SPARTAC study (N Engl J Med 2013;368:207-17 and [2]), we will investigate the development of glycan-binding HIV broadly neutralizing antibodies (bnAbs) during infection using in vitro neutralization assays, antigen-specific B cell sorting and antibody cloning, glycan array analysis, and next generation sequencing of antibody genes and HIV Envelope. We will determine how the viral Envelope evolution guides and directs bnAb development in these HIV-infected individuals and the role pre-existing anti-glycan antibody responses play in bnAb development. Ultimately these studies will be used to design immunogens and immunization strategies aimed at re-eliciting these bnAbs through vaccination.

One representative publication from each co-supervisor:

• L.A. Granger, I. Huettner, F. Debeljak, P. Kaleebu, M. Schechter, G. Tambussi, J. Weber, J.M. Miro, R. Phillips, A. Babiker, S. Fidler, J. Frater, J. Fox, K.J. Doores#, Broadly neutralizing antibody responses in the longitudinal primary HIV-1 infection SPARTAC cohort, AIDS, 2021, 10.1097/QAD.0000000000002988.

• L. M. Walker,* M. Huber,* K. J. Doores,* E. Falkowska, R. Pejchal, J.-P. Julien, S.-K. Wang, A. Ramos, P. Y. Chan-Hui, M. Moyle, J. L. Mitcham, P. W. Hammond, O. A. Olsen, P. Phung, S. Fling, C.-H. Wong, S. Phogat, T. Wrin, M. D. Simek, Protocol G Principal Investigators, W. C. Koff, I. A. Wilson, D. R. Burton, P. Poignard, Broad neutralization coverage of HIV by multiple highly potent antibodies, Nature, 2011, 477, 466-470.