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.
Highlights
The brutal attack on humanity by HIV-1 has proven to be distressingly difficult to counter
The possibility that blocking CD4 downregulation could have a positive impact on HIV-1 pathogenesis is supported by the example of an long term non-progressors (LTNP) infected by a HIV-1 with a uniquely defective Nef
Anti-HIV-1 drugs rapidly become ineffective unless administered in multi-drug combinations
Summary
The brutal attack on humanity by HIV-1 has proven to be distressingly difficult to counter. The possibility that blocking CD4 downregulation could have a positive impact on HIV-1 pathogenesis is supported by the example of an LTNP infected by a HIV-1 with a uniquely defective Nef. Carl et al reported a non-progressor (12 years without a decline in CD4+ T cells, but relatively high viral loads of 15,000 to 55,000 copies/ml) with a small deletion in Nef and a compensating duplication [87]. Incorporating the duplication into the deletion bearing Nef gave a partially functional protein that had restored enhancement of infectivity, MHCI downregulation, and protein expression but remained defective for CD4 downregulation The suggestion from this one patient is that an HIV-1 lacking a Nef functional for CD4 downregulation is greatly reduced in its pathogenic potential. As knowledge of the functions of Vif and other HIV-1 accessory proteins grows superior schemes involving combinations of inactivated genes may become apparent for attenuating HIV-1
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