Suppression of HIV-1 infection by a small molecule inhibitor of the ATM kinase

Abstract

Chemotherapy that is used to treat human immunodeficiency virus type-1 (HIV-1) infection focuses primarily on targeting virally encoded proteins. However, the combination of a short retroviral life cycle and high mutation rate leads to the selection of drug-resistant HIV-1 variants. One way to address this problem is to inhibit non-essential host cell proteins that are required for viral replication. Here we show that the activity of HIV-1 integrase stimulates an ataxia-telangiectasia-mutated (ATM)-dependent DNA damage response, and that a deficiency of this ATM kinase sensitizes cells to retrovirus-induced cell death. Consistent with these observations, we demonstrate that a novel and specific small molecule inhibitor of ATM kinase activity, KU-55933, is capable of suppressing the replication of both wild-type and drug-resistant HIV-1.

HIV-1 Vpr induces ATM-dependent cellular signal with enhanced homologous recombination

“…Vpr expression enhances the rate of HR, but several reports suggest that NHEJ rather than HR contributes to viral infection (Daniel et al, 1999;Li et al, 2001;Jeanson et al, 2002;Lau et al, 2005). Additionally, Rad52, a cellular component of HR, was shown to work as a suppressive factor for HIV-1 transduction (Lau et al, 2004).…”

“…This phenomenon has been explained by delayed progression at the G2/M phase due to DSBs. Additionally, caffeine and caffeine-related methylxanthines are known to impair HIV-1 infection (Nunnari et al, 2005), and an ATM inhibitor, KU55933, is known to decrease the integration of viral DNA into host genome (Lau et al, 2005). These observations suggest that a DSB-induced cellular signal, not HR, is important for viral integration, and that Vpr-induced DSB contributes to efficient viral integration in an ATM-dependent manner.…”

“…The synthesis of linear HIV-1 DNA in the cytoplasm by reverse transcription and the integration process of HIV-1 DNA into the host genome are thought to be possible triggers for the DNA-damage signals (Lau et al, 2004(Lau et al, , 2005. When chromosomal DNA is damaged (DSB; DNA double-strand break), two kinds of kinases (ATM and ATR) are initially activated to exert checkpoint control on cell cycle (Abraham, 2001).…”

“…When caffeine, which is known to inhibit both ATR and ATM, is administered in conjugation with the viral infection, the integration of viral DNA into the host genome is impaired . Additionally, data showing that the recently developed ATM inhibitor KU55933 decreased the copy number of the integrated HIV-1 DNAs strongly suggest that an ATM-dependent signal has a key role in viral transduction (Lau et al, 2005). In addition to the mechanism of viral infection, HIV-1-induced DSBs or their signals have an impact on the approaching AIDS pathogenesis, especially for cancer development.…”

Pro-apoptotic function of checkpoint kinase-2 in syncytia elicited by the HIV-1 envelope

“…It has been shown that the integration of the HIV-1 genome into host chromosomes involves the induction of DNA lesions that lead to the activation of ATM and that rely on ATM-dependent repair processes to be resolved. 38 However, the experimental system used here was virus-free, meaning that other mechanisms must come into action. We speculate that illicit cell fusion that affects proliferating, asynchronous cell populations, leads to a mixture of completely and partially replicated genomes stimulating a massive DNA damage response.…”