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Deciphering the molecular basis of unusually high neutralization resistance in a tier 3 HIV-1 strain

Deciphering the molecular basis of unusually high neutralization resistance in a tier 3 HIV-1 strain

Understanding the mechanisms used by HIV-1 to evade antibody neutralization may contribute to the design of a high-coverage vaccine. The tier 3 (highly neutralization-resistant) virus, 253-11, is poorly recognized by subtype-matched and subtype C sera, even when compared to other tier 3 viruses, and is also recognized poorly by V3/glycan targeting monoclonal antibodies. We found that sequence polymorphism in the V3 loop and N-linked glycosylation sites only marginally contribute to the high neutralization resistance of 253-11. Interestingly, the 253-11 membrane proximal external region (MPER) is rarely recognized by sera in the context of the wild-type virus, but is commonly recognized in the context of an HIV-2 chimeric virus. Mutations in the 253-11 MPER – which were previously reported to increase the lifetime of the pre-fusion Envelope (Env) conformation –affected the resistance of 253-11 to antibodies targeting various epitopes on HIV-1 Env and destabilized its otherwise stable, closed trimer structure. To gain insight into the structure of 253-11, we constructed and crystallized a recombinant 253-11 SOSIP trimer, the first crystal structure of a tier 3 SOSIP trimer from chronic infection. The resulting structure revealed that the heptad repeat helices in gp41 are drawn closer to the trimer axis and that gp120 protomers also showed a relatively compact disposition around the trimer axis. These observations give substantial insight into the structure of an envelope spike from a tier 3 virus and into possible mechanisms that may contribute to its unusually high neutralization resistance.

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