Interactions of the HIV/SIV Pathogenicity Factor Nef with SH3 Domain-Containing Host Cell Proteins

A bewildering number of host cell proteins associated with Nef can be found in the literature and in the public protein interaction databases. However, only in a few of these cases, including binding of Nef to certain Src homology-3 (SH3) domain proteins, is the interaction understood in any molecular detail or even known to be direct. Indeed, SH3 binding capacity by Nef is required for many of the other protein interactions to take place, suggesting that a large proportion of the latter is indirectly coupled to Nef via an SH3 protein. Accordingly, the proline-rich SH3 binding site, the “PxxP motif”, is one of the key functional determinants of Nef. It is highly conserved among the lentiviral Nef proteins, and mutations disrupting it abrogate the majority of the known effects of Nef on host cell physiology. This review summarizes the current understanding as well as the outstanding gaps in our knowledge regarding the relevant SH3 protein partners and SH3-dependent cellular functions of Nef. The roles of these interactions in the pathogenesis of AIDS and their potential as targets for antiviral drug development are also discussed.