HIV Antibody Immunology
Group leader: Jeffrey Dorfman
Phone: +27 21 406 6645
Office: Falmouth 3.28 (entrance 2, use lift to floor 3)
Our laboratory studies the interplay between antibody responses and immune escape by HIV-1. Understanding the mechanisms used by HIV-1 to evade antibody neutralization may contribute to the design of a high-coverage vaccine. We fund that the 253-11 virus is poorly neutralized by subtype-matched and subtype C sera, even when compared to other Tier 3 (highly neutralisazation-resistant) viruses. Additionally, its membrane proximal external region (MPER) is rarely recognized in the context of the native virus, even though it is commonly recognized in the context of an HIV-2 chimeric virus. Mutations intended to alter cell fusion/entry kinetics and increase the lifetime of the open conformation of Env found before cell fusion increase the sensitivity of the virus to sera and most monoclonal antibodies against various epitopes. However, strikingly, these mutations decrease sensitivity to the conformation-dependent antibody, PG9, leading us to hypothesize that they destabilize the trimer structure, and that it is a compact Env structure that may exclude many potentially neutralizing antibodies. The recombinant 253-11 Env SOSIP, intended to mimic the structure of a functional Env trimeric spike, expresses trimer in high yields, has a high melting temperature, and exhibits a predominantly closed conformation. In summary, 253-11 was found to have an unusually compact Env trimer, suggesting a novel understanding of how a virus can achieve high neutralization resistance. Importantly, neutralization resistance and Env compactness of this Tier 3 virus are properties that can be transferred to a recombinant SOSIP trimer construct, thus enabling future studies of Tier 3 Env structure and immunogenicity. Together, these insights lead to a better understanding of HIV-1 immune evasion that may guide vaccine design.
Other projects include:
- The impact of donor HIV-1 genital tract compartmentalization on the transmission bottleneck
- Chinks in the glycan armor of HIV-1 Envelope part I: implications for immune escape
- Autoreactivity of anti-HIV-1 neutralizing antibodies does not prevent broad antibody responses
- Diversity of HIV-1 group M: Are 9 subtypes enough?