Abstract
The success of many current vaccines relies on a formulation that incorporates an immune activating adjuvant. This will hold true for the design of a successful therapeutic HIV vaccine targeted at controlling reactivated virus following cessation of combined antiretroviral therapy (cART). The HIV accessory protein Nef functions by interfering with HIV antigen presentation through the major histocompatibility complex I (MHC-I) pathway thereby suppressing CD8+ cytotoxic T cell (CTL)-mediated killing of HIV infected cells. Thus, this important impediment to HIV vaccine success must be circumvented. This review covers our current knowledge of Nef inhibitors that may serve as immune adjuvants that will specifically restore and enhance CTL-mediated killing of reactivated HIV infected cells as part of an overall vaccine strategy to affect a cure for HIV infection.
Highlights
Over the last 25 years, combined antiretroviral therapy (cART) has evolved into a highly effective therapy that prolongs the lifespan of HIV infected individuals
Due to Nef’s primary role in the pathogenesis of HIV-1, the identification of novel small molecules that block key aspects of Nef function creates an important opportunity for the generation of a new class of molecular adjuvants that will augment current therapeutic vaccine approaches such that maximal anti-HIV cytotoxic T-lymphocyte (CTL) activity can be achieved
Current efforts to generate and test a second generation of 2c-like Nef inhibitors with greater affinity for the Nef–Src Family Kinase (SFK) interface are under way
Summary
Over the last 25 years, cART has evolved into a highly effective therapy that prolongs the lifespan of HIV infected individuals. An integral portion of this strategy is the reactivation of latent virus (shock) and the subsequent elimination of the cells producing the reawakened HIV (kill) by the immune response. HIV-1 Nef suppresses MHC-I antigen presentation in infected cells thereby blunting any therapeutic HIV vaccine efficacy.
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