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

作者：Bermejo Mercedes; Rosa Lopez Huertas Maria; Hedgpeth Joe; Mateos Elena; Rodriguez Mora Sara; Jose Maleno Maria; Plana Montserrat; Swindle John; Alcami Jose; Coiras Mayte^*

来源：Biochemical Pharmacology, 2015, 94(4): 241-256.

DOI：10.1016/j.bcp.2015.02.009

• HIV-1
• Protein kinase C theta
• SAMHD1
• Antiretroviral therapy
• Latent reservoir

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 (theta), which is involved in T-cell proliferation, as well as NF-kappa B, NF-AT, and AP-1 activation. We found that PKC theta activity increased viral replication, but also that HIV-1 induced higher activation of PKC theta in infected CD4+ T cells, creating a feedback loop. Therefore, specific inhibition of PKC theta activity could contribute to control HIV-1 replication. We tested the efficacy of seven PKC theta 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 PKC theta 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 that would increase the reservoir size. CGX1079 and CGX0471 did not completely abrogate T-cell functions such as proliferation and CD8-mediated release of IFN-gamma in PBMCs from HIV-infected patients, thereby avoiding general immunosuppresion. Consequently, using PKC theta inhibitors as adjuvant of antiretroviral therapy in recently infected patients would decrease the pool of activated CD4+ T cells, thwarting proviral integration and reducing the reservoir size.

• 出版日期2015-4-15