Highly activated p53 contributes to selectively increased apoptosis of latently HIV-1 infected cells upon treatment of anticancer drugs

Abstract

BackgroundDespite the successful inhibition of human immunodeficiency virus type 1 (HIV-1) replication by combination antiretroviral therapy, cells latently infected with HIV-1 remaining in patients are a major obstacle for eradication of HIV-1 infection. The tumor suppressor factor p53 is activated by HIV-1 infection, and restricts HIV-1 replication. However, a therapeutic strategy based on p53 activity has not been considered for elimination of latently infected cells.MethodsApoptotic cells were analyzed using flow cytometry with anti-annexin A5-FITC Ab and PI staining upon treatment of anticancer drugs. The expression and activation of p53 and apoptotic molecules in latently HIV-1-infected T cells were compared using Western blot analysis. The role of p53 in the anticancer drug treatment-induced apoptosis of cells latently infected with HIV-1 was determined by knock-down experiment using siRNA against p53.ResultsUpon treatment with 5-fluorouracil (5-FU), apoptosis was increased in latently infected ACH2 cells encoding competent p53 compared with uninfected parent A3.01 cells, while the apoptosis of latently infected p53 null J1.1 cells was less than that of uninfected cells. Treatment with 5-FU increased the levels of cleaved caspase-3 and PARP in ACH2 cells compared with uninfected and latently infected p53 null J1.1 cells. The levels of expression and activation of p53 were higher in both latently infected ACH2 and NCHA2 cells than in uninfected cells. Furthermore, the activation levels of p53 in both cells were further increased upon 5-FU treatment. Consistent with p53 status, apoptosis was markedly increased in ACH2 and NCHA2 cells compared with uninfected and latently infected J1.1 cells upon treatment with other anticancer drugs such as doxorubicin and etoposide. Inhibition of p53 in cells with latent HIV-1 infection diminished apoptosis upon 5-FU treatment.ConclusionEvidence described here indicate that when treated with anticancer drugs, apoptosis of cells with latent HIV-1 infection was increased via the p53 activation pathway and may provide information for application of anticancer drugs to selectively eliminate HIV-1 reservoirs.

Synergistic activation of p53 by actinomycin D and nutlin-3a is associated with the upregulation of crucial regulators and effectors of innate immunity

“…Thus, the data presented in this paper and the observations made by others support the notion that the innate immunity is the stress-response system strongly influenced by p53. Moreover, upregulation of antiviral genes by CPT or A + N is another observation in the growing body of evidence that anticancer chemotherapeutic agents have strong antiviral properties resulting from upregulation innate immunity genes [55]. This property of anticancer drugs must be carefully considered when planning for the anticancer strategies combining the use of oncolytic virotherapy with chemotherapeutic agents [56].…”

Hedgehog Signaling: Implications in Cancers and Viral Infections

“…The human homolog of a member of the GLI oncogene family, GLI2 (also termed hGLI2), helps HTLV1 infection progression as the simultaneous binding of hGLI2 and CREB seems critical for TAX protein to activate transcription [240]. HIV [241], HCV [242], HBV [243,244], EBV [245], and KSHV [246] utilize MYC and cellular STAT3 for infected cell proliferation, the persistence of herpesviruses latency, and inhibition of viral reactivation. HIV [247], HCV [248], HBV [249], EBV and KSHV [250,251] infected cells secrete cytokines and chemokines to regulate viral pathogenesis, evade host immune response (Toll-like receptors; TLRs and inflammasome), angiogenesis, and selectively chemoattracts T cells, activation and migration of immune cells.…”

p53 and the Viral Connection: Back into the Future ‡

“…It was found that by mediating DNA demethylation in host cells, 5-aza led to several outcomes; on the one hand, it reduced the expression of HPV genes and on the other hand, it caused p53 protein stabilization that in turn induced p53-dependent apoptosis [ 74 ]. Others have shown that treatment with anticancer chemotherapeutic agents, such as 5-fluorouracil (5-FU), can be used also against HIV-1 latently-infected T-cells, since 5-FU also stabilizes p53 leading to increased levels of p53-dependent apoptosis [ 75 ].…”