The activity of Nef on HIV-1 infectivity

Abstract

The replication and pathogenicity of lentiviruses is crucially modulated by "auxiliary proteins" which are expressed in addition to the canonical retroviral ORFs gag, pol, and env. Strategies to inhibit the activity of such proteins are often sought and proposed as possible additions to increase efficacy of the traditional antiretroviral therapy. This requires the acquisition of an in-depth knowledge of the molecular mechanisms underlying their function. The Nef auxiliary protein is expressed uniquely by primate lentiviruses and plays an important role in virus replication in vivo and in the onset of AIDS. Among its several activities Nef enhances the intrinsic infectivity of progeny virions through a mechanism which remains today enigmatic. Here we review the current knowledge surrounding such activity and we discuss its possible role in HIV biology.

Keywords: AIDS; HIV; Nef; auxiliary proteins; retrovirus infectivity.

FIGURE 1

Cellular or virus-borne: localization of Nef activity on virus infectivity. Nef is expressed in infected cells and incorporated into virions. Given the profound imprint of Nef on the biology of infected cells, it may regulate a cellular function in virus-producing cells that favors virus infectivity (1). The fact that virus-borne Nef molecules are processed during maturation also suggests that cleaved molecules may play a role when virions hit target cells (2). Recent findings tend to favor the former hypothesis.

FIGURE 2

Possible mechanisms responsible for the differential infectivity of Nef+ and Nef- viruses. (A), Nef- virions may acquire a defect during biogenesis which could be either the packaging of an inhibitor into virions (black shape), or the exclusion of a cofactor (not shown). This defect might then prevent the recruitment of cofactor (yellow shape) or be the target of an inhibitor (not shown) in target cells. (B,C) The effect of Nef on virus infectivity is evident when virus is produced from Nef-responsive cells, in which Nef regulates such inhibitor or promote virus assembly to subcellular locations where the defect is not acquired (B). (D–F) In contrast, Nef-non-responsive producer cells generate Nef+ and Nef- viruses with similar infectivities (F). Two possibilities may explain this phenotype: Nef fails to protect the virus from the defect [D,F(1), Virions have suboptimal infectivity even in the presence of Nef]; alternatively, producer cells lack the cause of the defect or target virus assembly away from inhibitors [E,F(2), Nef- virus already has optimal infectivity].