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

Lisa N McKernan1, David Momjian, Joseph Kulkosky

  • 1Department of Biology, Chestnut Hill College, Philadelphia, PA 19118, USA.

Advances in Virology
|April 14, 2012
PubMed

Insights

Eradicating latent HIV-1 reservoirs is challenging. Modulating the protein kinase C (PKC) pathway with small molecules shows promise for reactivating latent HIV-1 and potentially eliminating reservoirs.

Area of Science:

  • Virology
  • Immunology
  • Pharmacology

Background:

  • Effective strategies to eliminate latent Human Immunodeficiency Virus type 1 (HIV-1) reservoirs are currently lacking.
  • Previous attempts at reservoir purging over a decade ago were unsuccessful, and research has since focused on understanding latency mechanisms.
  • Novel molecular antagonists for HIV-1 latency exist but require human trials for reservoir ablation efficacy.

Purpose of the Study:

  • To review the protein kinase C (PKC) pathway as a potential target for HIV-1 reservoir eradication.
  • To explore small molecular agents that modulate the PKC pathway to induce latent HIV-1 expression.

Main Methods:

  • Review of existing literature on the PKC pathway and its role in HIV-1 latency.
  • Analysis of small molecular agents targeting the PKC pathway.
  • Examination of preclinical and clinical data for PKC modulators.

Main Results:

  • The protein kinase C (PKC) pathway can be modulated by small molecules to induce the expression of latent HIV-1.
  • Some PKC-modulating agents have demonstrated tolerable side effects in cancer treatments.
  • No PKC-targeting agents have yet been tested in human trials specifically for HIV-1 reservoir ablation.

Conclusions:

  • Modulation of the PKC pathway represents a potential therapeutic strategy for HIV-1 reservoir eradication.
  • Further clinical investigation of PKC pathway modulators is warranted for HIV-1 cure research.

Related Concept Videos

cAMP-dependent Protein Kinase Pathways01:25

cAMP-dependent Protein Kinase Pathways

Cyclic Adenosine Monophosphate (cAMP) is an essential second messenger that activates protein kinase A (PKA) and regulates various biological processes. A single epinephrine molecule binds to GPCR and activates several heterotrimeric G proteins, each stimulating multiple adenylyl cyclase, amplifying the signal, and synthesizing large numbers of cAMP molecules. Small changes in cAMP concentration affect PKA activity. The binding of four cAMP molecules induces a conformational change in PKA,...
Retrovirus Life Cycles01:10

Retrovirus Life Cycles

Retroviruses have a single-stranded RNA genome that undergoes a special form of replication. Once the retrovirus has entered the host cell, an enzyme called reverse transcriptase synthesizes double-stranded DNA from the retroviral RNA genome. This DNA copy of the genome is then integrated into the host’s genome inside the nucleus via an enzyme called integrase. Consequently, the retroviral genome is transcribed into RNA whenever the host’s genome is transcribed, allowing the retrovirus to...
The JAK-STAT Signaling Pathway01:20

The JAK-STAT Signaling Pathway

Several cytokine receptors have tightly bound Janus kinase or JAK proteins attached at their cytosolic tail. Small signaling molecules such as cytokines, growth hormones, or prolactins bind to the cytokine receptors and initiate their dimerization. The dimerization brings the cytosolic JAKs together that trans-phosphorylate and activates each other. The activated JAKs now phosphorylate cytosolic tails of the cytokine receptors, which serve as binding sites for adaptor proteins such as  SH2...
Inhibitors of Viral Protein Synthesis01:30

Inhibitors of Viral Protein Synthesis

Protein synthesis is indispensable for viral replication, as viruses lack the cellular machinery required for this process and must hijack the host's translational apparatus. In response, host cells deploy a critical innate immune defense involving interferons, specialized cytokines that play a central role in inhibiting viral propagation.Upon viral detection, infected cells release interferons that bind to receptors on adjacent uninfected cells, activating the JAK-STAT signaling pathway and...
Inhibition of Cdk Activity02:34

Inhibition of Cdk Activity

The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
Interactions Between Signaling Pathways01:19

Interactions Between Signaling Pathways

Signaling cascades usually lack linearity. Multiple pathways interact and regulate one another, allowing cells to integrate and respond to diverse environmental stimuli.
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...