The aim of this project is to select peptide epitopes that mimic neutralization sensitive domains of HIV-1 envelope and may function as candidate HIV-1 vaccines. To date, efforts to develop a truly prophylactic HIV-1 vaccine have been hindered by difficult y in identifying immunogens that elicit broadly neutralizing antibodies. This lack of significant cross-protection raises further concerns on the capacity of classical Env-based vaccines to afford substantial protection against field isolates. Indeed, curr ent unmodified gp120 or gp140 envelope-based vaccines in human subjects have shown little or no protection from heterologous HIV-1 isolates such as would be encountered in the field. This indicates that vaccine trials with currently available immunogens wi ll afford low percentages of protection with a large number of vaccine breakthroughs and will raise ethical and financial issues concerning the treatment of any volunteers who become infected. It is of the highest priority that a focused effort is undertak en to develop novel Env antigens capable of inducing broad and potent neutralising antibodies to a wide variety of strains. Consistently, this consortium is developing a new generation of Env antigens based on complex but conserved epitopes to induce broad neutralising antibodies. This objective will be achieved by two complementary strategies: a. Screening of Random Peptide Libraries with novel MAbs that neutralise primary HIV-1 isolates assigned to distinct clades; b. designing of 30-40 amino acid peptide s that mimic discontinuous regions of gp120 and gp41 that are sensitive to neutralization by antibodies and are conserved among HIV strains of distinct clades. These include the CD4-binding domain, the bridging sheet and the pre-fusogenic harpin loop of gp 41. In this two years proposal the novel vaccine candidates will be validated in mice; however, the Consortium is endowed with the facilities and resources to proceed to monkeys models of HIV-1 infection.
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