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Vpu Matchmakers as a Therapeutic Strategy for HIV Infection

M. Montal

Published 2009 in PLoS Pathogens

ABSTRACT

Chemoprophylaxis and therapeutic intervention of the HIV epidemic requires understanding the mechanisms by which newly assembled HIV-1 virions are released from infected cells. This knowledge may prove diagnostic in identifying unsuspected sites for intervention and plausible strategies for targeted drug delivery. It is imperative, urgent, and ethical to uncover reliable and selective inhibitors of progeny virus release [1]. Vpu, an accessory membrane protein from the AIDS-associated virus HIV-1 [2], folds into two distinct structural domains with different biological activities: a transmembrane (TM) a-helical domain involved in the budding of new virions from infected cells, and a cytoplasmic domain encompassing two amphipathic helices, which is implicated in CD4 degradation [3,4]. Without Vpu, the HIV-1 virus remains attached to the surface of the human cell in which it has replicated. This activity of Vpu requires an intact TM ahelical domain [5,6]. And, it is known that oligomerization of the Vpu TM domain results in the formation of sequencespecific, cation-selective channels [6–9]. The molecular mechanism by which Vpu facilitates virion release remains unclear [2]. However, the recent discovery that Vpu neutralizes the effect of tetherin (B cell stromal antigen 2, BST-2/HM1.24) has provided insights into the molecular basis of its action [10,11]. Tetherin is an interferon-induced host cell membrane protein that blocks the release of HIV-1 virions from the cell surface [10,11]. This finding posits the notion that abrogation of Vpu function with the consequent suppression of new viable virus release from the host cell surface is a plausible therapeutic strategy in the treatment of HIV/ AIDS.

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