One way to lure HIV-1 from its hiding place.

It is thought that the latent reservoir contributes to the persistence of HIV-1 and blunts the overall potential of highly active anti-retroviral therapy (HAART).  Scientist believe that new pharmacological interventions, such as a Protein Kinase C (PKC) activators called Prostratin, can be incorporated into a two-step strategy in which the elusive HIV reservoir is coaxed into its bioactive form, and then targeted by HAART (Mbonye and Karn 2011).

When Prostratin binds to the N-terminus of a muscurinic 1 receptor, it induces a conformational change in the receptor that interacts with the G-coupled protein and leads to the dissociation of the a-subunit (Boron and Boulpaep 2011).  The a-subunit then activates the intracellular enzyme phospholipase C into its catalytically active form.  Phospholipase C can then cleave a normal phospholipids embedded in the lipid membrane of the T cell called PIP2 into inositoltrisphosphate (IP3) and diacylglycerol (DAG) products (Boron and Boulpaep 2011).  IP3 is a molecule that is able to open intracellular calcium stores and an increase concentration of Ca2+, which increases the concentration of activated PKC (Figure 1).

Figure 1. This figure illustrates part one of a complicated signaling cascade that is elicited when Prostratin, a ligand mimetic, is bound to a G-Protein Coupled Receptor. The release of intracellular calcium ions from the endoplasmic reticulum increases the concentration of activated PKC.  Activated PKC can then activate Nf-kB.    

Prostratin elicits this PKC signaling pathway and activates Nf-kB.  Active Nf-kB in CD4+ T cells helps to promote proviral transcription. By increasing the concentration of active PKC, there is more of a capacity to phosphorylate IkB kinase, which in turn phosphorylates Inhibitor of Kappa B Alpha (IkBa) (Mbonye and Karn 2011).  IkBa is an inhibitory protein that masks the nuclear localization signal (NLS) of p50/p56 heterodimer form of NF-kB. The heterodimer form of NF-kB serves as a transcriptional activator and binds to NF-kB response element on the promoter region of the provirus and recruits chromatin remodeling machinery.  This machinery disassociates the viral DNA from a histone protein called Nuc-1 and liberates the promoter region for transcription (Mbonye and Karn 2011).

PKC activators ultimately antagonizes HIV latency and serves as a tool to reactivate HIV.  Although there are multiple ways HIV maintains latency, by developing more and more pharmacological strategies to liberate quiescent HIV, scientist hope to potentiate HAART to a curative agent.

AIDS Research Alliance. 2014. Prostratin: a Potential Cure Strategy. [Internet]. Available from: aidsresearch.org/cure-research/prostratin/

Boron WF, Boulpaep EL. 2011. Medical Physiology. 2nd ed. New York: Saunders.

Mobonye U, Karn J. 2011. Control of HIV Latency by Epigenetic and Non-Epigenetic Mechanisms. National Institutes of Health Online. [Internet]. Available from: www.retrovirology.com/content/6/1/111 .