HIV-1 Nef: at the crossroads

Abstract

The development of anti-virals has blunted the AIDS epidemic in the Western world but globally the epidemic has not been curtailed. Standard vaccines have not worked, and attenuated vaccines are not being developed because of safety concerns. Interest in attenuated vaccines has centered on isolated cases of patients infected with HIV-1 containing a deleted nef gene. Nef is a multifunctional accessory protein that is necessary for full HIV-1 virulence. Unfortunately, some patients infected with the nef-deleted virus eventually lose their CD4+ T cells to levels indicating progression to AIDS. 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.

Figure 1

Diagram illustrating the functions of Nef discussed in the text.Lower right (Red), Nef removes CD4 from the cell surface. Two processes are shown. To the right Nef is attached to the plasma membrane through its myristoyl group (squiggle) and is detaching Lck from the cytoplasmic tail of CD4. As indicated by "?" both the site and mechanism of this process are unknown and may be indirect. To the left Lck has been disassociated from the cytoplasmic tail of CD4 and Nef is attached to the plasma membrane by its myristoyl group and the cytoplasmic tail of CD4. AP-2 binding facilitates the formation of a clathrin coated pit that leads to the internalization of CD4. Left (Yellow), Nef downregulates MHCI from the surface of the infected cell. Nef binds to the cytoplasmic tail of MHCI (triple line) and AP-1 in the TGN to divert MHCI from the default pathway to the plasma membrane. Top (Orange), Nef activates Pak2. The identities of the other protein(s) in the Nef/Pak2 complex are not known as shown by the unidentified protein (?). The cellular site of the activation is also not known though the plasma membrane has been proposed. Center (Pink), Nef binds to and activates Hck. The central (cytosolic) location of Nef bound to Hck with no attachment of the myristate to a membrane indicates that the activation of Hck is the only Nef function that does not require this post-translational modification. Upper right (Blue), Nef enhances the intrinsic infectivity of the HIV-1 virion. Three proposed mechanisms that limit HIV-1 infectivity, but are overcome by Nef are presented. The top virion fusing with the cell membrane is attempting to insert the viral core into the target cell but the entry of the core is blocked by cortical actin. The lower virion entering the cell is able to efficiently pass through the cortical actin but is subject to proteosomal degradation upon entry. The extracelluar virion is being prevented from attaching to the target cell by the presence of an unknown protein (X) that prevents Env (O) binding to target cell CD4.