In vivo analysis of Nef function

The nef gene is present in all primate lentiviruses (HIV-1, HIV-2, and SIVs). In vivo, Nef has been shown to be a major determinant of virus pathogenicity. In vitro, many different Nef activities have been reported, including CD4 and MHC I downregulation, enhanced virion infectivity, and T-cell activation. These four different activities have been extensively investigated and appear to increase the pathogenicity of the virus. However, the contribution that these activities (individually or together) make to the in vivo phenotype has not been elucidated. The mechanism(s) by which Nef modulates distinct host cell properties has provided great insights into the intricate interaction between virus and host. In this manuscript, we review the different model systems that have been used to study Nef function in vivo and the information that they have provided regarding the best characterized in vitro Nef activities. The knowledge that has been accumulated has provided clues to our understanding of Nef function but they have also left us with many unanswered questions that should be the focus of future in vivo analysis of Nef function.