Analysis of protein kinase C theta inhibitors for the control of HIV-1 replication in human CD4+ T cells reveals an effect on retrotranscription in addition to viral transcription

Biochemical Pharmacology
Mercedes BermejoMayte Coiras

Abstract

HIV-1 infection cannot be cured due to reservoirs formed early after infection. Decreasing the massive CD4+ T cell activation that occurs at the beginning of the disease would delay reservoir seeding, providing a better prognosis for patients. CD4+ T cell activation is mediated by protein kinase C (PKC) theta (θ), which is involved in T-cell proliferation, as well as NF-κB, NF-AT, and AP-1 activation. We found that PKCθ activity increased viral replication, but also that HIV-1 induced higher activation of PKCθ in infected CD4+ T cells, creating a feedback loop. Therefore, specific inhibition of PKCθ activity could contribute to control HIV-1 replication. We tested the efficacy of seven PKCθ specific inhibitors to control HIV-1 replication in CD4+ T cells and selected two of the more potent and safer: CGX1079 and CGX0471. They reduced PKCθ phosphorylation at T538 and its translocation to the plasma membrane, which correlated with decreased HIV-1 retrotranscription through partial inhibition of SAMHD1 antiviral activity, rendering lower proviral integration. CGX1079 and CGX0471 also interfered with viral transcription, which would reduce the production of new virions, as well as the subsequent spread and infection of new targets ...Continue Reading

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Citations

Mar 15, 2016·Frontiers in Immunology·María Rosa López-HuertasMayte Coiras
Nov 4, 2015·Frontiers in Immunology·Vedran BrezarNabila Seddiki
Aug 19, 2015·Frontiers in Immunology·Chansavath Phetsouphanh, Anthony D Kelleher
Apr 8, 2017·Expert Opinion on Drug Safety·Mayte CoirasJosé Alcamí
Dec 24, 2018·Frontiers in Immunology·Marta Colomer-LluchJulia G Prado
Sep 3, 2019·Biochemical Pharmacology·María SalgadoMayte Coiras

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