HIV-1 Nef: at the crossroads

This renders the possibility of an attenuated HIV-1 based solely on a deleted nef remote. In this review we discuss the knowledge gained both from the study of these patients and from in vitro investigations of Nef function to assess the possibility of developing new anti-HIV-1 drugs based on Nef. Specifically, we consider CD4 downregulation, major histocompatibility complex I downregulation, Pak2 activation, and enhancement of virion infectivity. We also consider the recent proposal that simian immunodeficiency viruses are non-pathogenic in their hosts because they have Nefs that downregulate CD3, but HIV-1 is pathogenic because its Nef fails to downregulate CD3. The possibility of incorporating the CD3 downregulation function into HIV-1 Nef as a therapeutic option is also considered. Finally, we conclude that inhibiting the CD4 downregulation function is the most promising Nef-targeted approach for developing a new anti-viral as a contribution to combating AIDS.The brutal attack on humanity by HIV-1 has proven to be distressingly difficult to counter. The best results at blunting the epidemic have been the development of anti-retrovirals (ARVs) that inhibit crucial HIV-1 functions. Unfortunately, the unique ability of HIV-1 to mutate and adapt [1,2] requires multiple drug treatments that are limited in their application by their side effects and their expense. Topically applied microbicides offer the possibility of prevention, but similar problems of toxicity, expense, and effective application apply here as well as with ARVs [3,4]. Vaccines have been a total failure and future prospects are dim [5-8].Well into the third decade of HIV-1 research the likelihood of finding an Achilles' heel for HIV-1 is remote. The virus is too highly adapted from its successful 70 year contest with the human immune system [9,10]. Accumulating small victories are the probable long term course for significantly curtailing the epidemic. Effective microbicides are desperately needed fo