Quentin Sattentau

We are interested in designing new immunogens to elicit neutralizing antibodies to conserved regions on the HIV-1 envelope glycoprotein (Env) spike. Env has evolved numerous antibody evasion mechanisms that make antibody-based vaccine design a formidable task. Amongst these mechanisms are structural and conformational instability, both of which render Env a difficult target for B cell recognition, and the immunodominance of highly variable regions, facilitating viral escape from antibody attack. We have adopted several parallel strategies to overcome these immune evasion mechanisms. Firstly, we are using chemical cross-linking to ‘lock’ the Env into a stable conformation that should extend in vivo half life and facilitate B cell recognition of conserved surfaces. Second we are using post-translational targeted addition of synthetic glycans to mask proteins surfaces with undesirable immunogenicity. Third, we are investigating appropaches to mimic small conserved glycopeptide epitopes of Env using synthetic glycopeptides, to focus the antibody response to these areas.

Since subunit vaccines require robust adjuvantation to elicit robust immune responses, we are in parallel characterising novel adjuvants for use with viral glycoproteins. We recently discovered a new family of adjuvant molecules called polyethyleneimine (PEI), well known for its nucleic acid transduction activity. PEI is a polycations, and has potent mucosal and systemic adjuvant activity with an immunological signature similar to, but more potent than, aluminium salts. PEI triggers both T cell and antibody responses by activating both the innate and adaptive arms of the immune response. We are currently studying the potential of PEI to adjuvant HIV-1 Env, and hope to investigate its ability to adjuvant bacterial antigens for immersion vaccination of fish. A second family of adjuvants is the carbomers, particularly carbopol, a group of cross-linked polyanions. These molecules activate a pro-inflammatory Th1-type immune response eliciting potent antibody and cytotoxic T cell responses. Again these may find utility in an HIV Env-based vaccine for generating neutralising antibody responses.

HIV-1 spreads with a host by two mechanisms – release of cell-free virions and directed cell-to-cell spread between contacting infected and uninfected cells. We have shown that cell-cell spread of HIV may confer advantages over cell-free spread, such as preferential infection of myeloid cells such as macrophages, more rapid viral replication and dissemination, and resistance to both neutralising antibodies and antiretroviral therapy. These findings have relevance to antibody-based vaccine design, therapeutic intervention, and the establishment and maintenance of viral reservoirs. We are continuing this work with the aim of better understanding how we might overcome or limit cell-to-cell spread to reduce viral reservoir formation and resistance to antibody attack.