Knowledge of the molecular structure of trimeric Env on intact viruses and delineating the mechanisms of cell-cell transmission are central to the design of effective immunogens and therapeutic agents to combat HIV/AIDS. We have continued to make significant progress towards these goals over the last year. Major advances we have made over the last year include: (i) discovery of variations in the type of virological synapses involved in mediating HIV transmission between different types of cell-cell contacts including T-cell-T-cell and T-cell-dendritic cell synapses;(ii) molecular structures of trimeric HIV-1 and SIV envelope glycoproteins from a large number of viral strains and from soluble immunogens;(iii) demonstration that soluble gp140 immunogens can display the same ligand-induced changes in conformation that are seen with native envelope glycoproteins;(iv) the unexpected finding that binding of trimeric envelope glycoproteins to a co-receptor mimic alone induces the same conformational changes as binding to CD4 and (v) structural evidence, at sub-nanometer resolution, of a novel, activated intermediate state of HIV where highly conserved, interior components of the viral spike are exposed, providing a template for the design of immunogens aimed at eliciting antibodies that could block HIV entry.
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