HIV - 1 Nef: At the Crossroads

John L Foster; J Victor Garcia

Disclosures

Retrovirology 

In This Article

Abstract and Introduction

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.

Introduction

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.[5,6,7,8]

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 for vaginal pre-exposure prophylaxis and post-exposure prophylaxis. New ARVs that inhibit an increasing number of viral processes are critical for treating already infected individuals. ARVs are potentially useful in prophylaxis as well. In this case topically applied drugs would ideally be different from drugs used for treating HIV-1 since topical application could lead to resistant strains of HIV-1.[3,4] Therefore, all possible targets for countering HIV-1 need to be considered. Given its central role in HIV pathogenesis, in this article we consider Nef as a potential anti-viral target for preventing or at least delaying pathogenesis.

Ironically, the overwhelming focus for a Nef-based therapeutic intervention has been the investigation of a nef-deleted attenuated virus vaccine. This interest resulted from a small number of cases of long term non-progressors (LTNP) whose viruses have irretrievable deletions in the nef gene.[11,12,13,14] Unfortunately, some individuals infected with the nef-deleted virus are slow progressors (SP) rendering a nef-deleted attenuated vaccine too dangerous. We will not review this aspect of the Nef field in detail since an excellent review has been recently published on the most important of these cases- the Sydney Blood Bank Cohort (SBBC).[15] We will discuss several aspects of SBBC and other cases that shed light on the role of Nef in the development of HIV-1 disease.

The lack of disease progression in patients whose HIV-1s are nef-deleted, defines Nef as a pathogenic factor. Whether Nef acts as a generalized enabler of high levels of replication or is directly pathogenic remains unresolved. In either case it would seem logical to investigate blocking Nef function in order to lessen the severity of HIV-1 disease. Though the idea of Nef as a target for drug intervention in HIV-1 disease has rarely been considered,[16,17] Betzi et al. have recently identified the first compounds that target Nef.[18] The major problem is the daunting complexity of Nef's multiple functions. Accordingly, we will discuss four intensely studied Nef activities and assess possible roles for each function in pathogenesis. These are CD4 downregulation, major histocompatibility complex I downregulation, activation of p21-activated protein kinase (Pak2), and enhancement of virion infectivity.[19] Each function is genetically separable from the others and therefore represents a distinct target for inhibiting Nef.[20,21] That each of these four functions is mechanistically distinct implies that an anti-Nef drug will not be able to debilitate Nef in general, but probably block only one or two. This makes it imperative to determine the Nef function most relevant to pathogenesis. In addition, we will discuss the possibility of a radical new approach to viral pathogenesis based on the recent model of simian and human lentivirus pathogenesis being controlled by the downregulation of CD3 by Nef.[22] Finally, we will conclude that an attenuated virus vaccine based solely on a Nef deletion is still remote, and that CD4 downregulation is the most promising target for attacking HIV-1 through Nef.

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