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Protein Kinase C: One Pathway towards the Eradication of Latent HIV-1 Reservoirs

DOI: 10.1155/2012/805347

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An effective means to eradicate latent reservoirs in HIV-1-infected individuals remains elusive. Attempts to purge these reservoirs were undertaken over a decade ago without success. The subsequent lapse in further clinical attempts since may have been justified as our knowledge of the mechanisms which underpin the latent state still evolves. Although additional novel molecular antagonists of HIV-1 latency have subsequently been reported, these candidate agents have not been tested in human trials for reservoir ablation. This review provides an overview of the protein kinase C (PKC) pathway which can be modulated by small molecular agents to induce the expression of latent HIV-1 from within infected reservoir cells. Some of these agents have been tested against select cancers with seemingly tolerable side effects. As such, modulation of the PKC pathway may yet be a viable mechanism toward HIV-1 reservoir eradication. 1. Introduction Administration of highly active anti-retroviral therapy (HAART) to HIV-1-infected individuals results in effective suppression of viral replication in metabolically active cells bearing integrated viral DNA. However, a small population of infected cells is refractive to HAART treatment as a consequence of being quiescent and/or not actively expressing virus products [1–5]. This small population of cells, comprised largely of infected CD4+ resting T cells, constitutes the HAART-persistent latent reservoir. Most cells in this silent reservoir have long half lives [6, 7] and are hidden from immune surveillance which permits them to remain as a stable source for de novo viral production upon reactivation. One strategy for eradication of this reservoir rests upon the premise that cellular activation with concomitant upregulation of viral expression will hasten its elimination [8–11]. Cellular activation typically shortens the half-life of a cell relative to its quiescent counterpart, and a cell, actively expressing viral antigens, would be a more favorable target for immune clearance [12]. Some time ago, several clinical trials were attempted to eradicate or diminish the presence of latent reservoirs using the cellular activators, OKT3 and IL-2, which primarily target T-cell responses [13–18]. These trials were ineffectual although genotypic alterations of reservoir virus in treated individuals were noted [19]. Nonetheless, these attempts clearly indicated that a broader armamentarium of agents or multiple clinical interventions were required to accomplish the elusive goal of complete reservoir eradication. The list of candidates

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