Despite decades of intense research, HIV and other retroviruses retain still surprisingly obscure features, which we need to understand. One of these features concerns Nef, a pathogenic factor of primate lentiviruses, crucial for virus replication and disease progression. This is a challenging lentiviral molecule, because of its extraordinary multifunctionality. If we know relatively well how Nef downregulates cell surface receptors, or activates T-cells and macrophages, we still do not understand how it promotes the infectivity power of virus particle. When HIV is derived from lymphoid cells, up to 98% of its infectious capacity can depend on Nef being expressed in producer cells, but we do not know how this occurs.
Despite its many functions already known, in Nef there is space for another activity which has gone unnoticed until now. I have recently unveiled the ability of Nef to increase HIV resistance, up to 50-fold and very specifically, to one of the most powerful and broad classes of neutralizing antibodies. This feature is genetically separable from other activities of Nef, and given its potential implications for pathogenesis in vivo, it deserves immediate attention.
While Nef is only present in primate lentiviruses, I have discovered that the activities on virus infectivity and neutralization are not unique to HIV and SIV, but also exerted by gammaretroviruses via a molecule called glycosylated gag (Glycogag) which has no sequence relation with Nef. I have recently shown that the two unrelated proteins share impressive functional similarity, which indicates a compelling case of convergent evolution and open the possibility that Nef and Glycogag are part of a novel class of fundamental retrovirus infectivity factors.
The research proposed here intends to unveil how these factors work and to reveal the significance of their role in vivo, to hopefully identify new strategies to fight virus infections.
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