Protein Kinase Cθ Is a Specific Target for Inhibition of the HIV Type 1 Replication in CD4+ T Lymphocytes

Integration of HIV-1 genome in CD4(+) T cells produces latent reservoirs with long half-life that impedes the eradication of the infection. Control of viral replication is essential to reduce the size of latent reservoirs, mainly during primary infection when HIV-1 infects CD4(+) T cells massively. The addition of immunosuppressive agents to highly active antiretroviral therapy during primary infection would suppress HIV-1 replication by limiting T cell activation, but these agents show potential risk for causing lymphoproliferative disorders. Selective inhibition of PKC theta, crucial for T cell function, would limit T cell activation and HIV-1 replication without causing general immunosuppression due to PKC theta being mostly expressed in T cells. Accordingly, the effect of rottlerin, a dose-dependent PKC theta inhibitor, on HIV-1 replication was analyzed in T cells. Rottlerin was able to reduce HIV-1 replication more than 20-fold in MT-2 (IC50 = 5.2 mu M) and Jurkat (IC50 = 2.2 mu M) cells and more than 4-fold in peripheral blood lymphocytes (IC50 = 4.4 mu M). Selective inhibition of PKC theta, but not PKC delta or -zeta, was observed at <6.0 mu M, decreasing the phosphorylation at residue Thr(538) on the kinase catalytic domain activation loop and avoiding PKC theta translocation to the lipid rafts. Consequently, the main effector at the end of PKC theta pathway, NF-kappa B, was repressed. Rottlerin also caused a significant inhibition of HIV-1 integration. Recently, several specific PKC theta inhibitors have been designed for the treatment of autoimmune diseases. Using these inhibitors in combination with highly active antiretroviral therapy during primary infection could be helpful to avoid massive viral infection and replication from infected CD4(+) T cells, reducing the reservoir size at early stages of the infection.